Oxygen linked pyrimidine derivatives

ABSTRACT

The present invention relates to pyrimidine compounds that are useful as anti-proliferative agents. More particularly, the present invention relates to oxygen linked and substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumors and cancers as well as other disorders or conditions related to or associated with kinases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of application Ser. No. 13/438,989,filed on Apr. 4, 2012, which is a Divisional of application Ser. No.12/093,867 filed on Oct. 21, 2008, which is a National Phase filingunder 35 U.S.C. §371 of PCT/SG2006/000352 filed on Nov. 15, 2006, andclaims priority to Provisional Patent Application No. 60/736,838, filedin the United States on Nov. 16, 2005, Provisional Patent ApplicationNo. 60/817,339, filed in the United States on Jun. 30, 2006, andProvisional Patent Application No. 60/851,283, filed in the UnitedStates on Oct. 13, 2006. The entire contents of each of theabove-applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to pyrimidine compounds that may be usefulas anti-proliferative agents. More particularly, the present inventionrelates to oxygen linked and substituted pyrimidine compounds, methodsfor their preparation, pharmaceutical compositions containing thesecompounds and uses of these compounds in the treatment of proliferativedisorders. These compounds may be useful as medicaments for thetreatment of a number of proliferative disorders including tumours andcancers as well as other conditions or disorders associated withkinases.

BACKGROUND OF THE INVENTION

Proliferative disorders such as cancer are characterised by theuncontrolled growth of cells within the body. As such proliferativedisorders generally involve an abnormality in the control of cell growthand/or division leading to the formation of tumour and ultimately death.Without wishing to be bound by theory it is thought that this is causedby the pathways that regulate cell growth and division being altered incancer cells. The alteration is such that the effects of these normalregulatory mechanisms in controlling cell growth and division eitherfails or is bypassed.

The uncontrolled cell growth and/or division ultimately proves fatal forthe patient as successive rounds of mutations on the part of the cellthen typically lead to the cancer cells having a selective advantageover normal healthy cells in the body of the patient leading to thecancer cells predominating in the cell mass of the patient. The cancercells then typically metastasize to colonize other tissues or parts ofthe body other than the part of origin of the cancer cell leading tosecondary tumours which eventually lead to organ failure and the deathof the patient. It is the difficulty in controlling the rapid cellgrowth and division that is characteristic of cancer cells that make ithard to come up with effective chemotherapeutic strategies.

A number of traditional treatments for proliferative disorders such ascancer seek to take advantage of their higher proliferative capacity andthus their higher sensitivity to DNA damage. Treatments that have beenutilised include ionizing radiation (γ-rays, X-rays and the like) aswell as cytotoxic agents such as bleomycin, cis-platin, vinblastine,cyclophosphamide, 5′-fluorouracil and methotrexate. These treatments allrely on causing damage to DNA and destabilisation of the chromosomalstructure eventually leading to death of the cancer cells.

The problem with many of these approaches is that they are non-selectivefor cancer cells and healthy cells can and often will be adverselyaffected by the treatment. This is hardly surprising given that thecellular mechanisms targeted by these strategies occur in healthy cellsas well as in cancer cells (although typically at slower rates) andmerely serves to highlight the difficulty in achieving successfultreatment of the cancer in the patient without causing irreparable harmto the healthy cells. As such with many of these treatments there can bedevastating side effects which can not only significantly reduce theshort term quality of life of the patient but may also have long termdetriments on the health of the patient should they survive the cancerattack.

Whilst some of the above problems have substantially been overcome bythe development of selective anti-cancer agents (such as tamoxifen) theeffectiveness of all chemotherapeutic agents is subject to thedevelopment of drug resistance by the cancer cells in the patient. Thedevelopment of drug resistance in the cancer cells of a patient tends tobe class specific and therefore if the cancer cells of a patient developdrug resistance to a class of anti-cancer drugs then all compoundswithin that class are typically rendered ineffective in the furthertreatment of that patient. As such in improving clinical outcomes forpatients the identification of alternative chemotherapeutic agents isessential in providing the oncologist with an arsenal of drugs that maybe used in any given situation.

The development of different classes of therapeutic agents is thereforeimportant as it can help avoid the development of drug resistance andcan also be used in combination therapies. Such combination therapiestypically involve the use of anti-cancer drugs with different propertiesand cellular targets which in turn tends to increase the overalleffectiveness of any chosen chemotherapy regime and limits thepossibility of drug resistance developing in the patient.

One of the major advances in cancer research has been the clinicalvalidation of molecularly targeted drugs that inhibit the activity ofprotein kinases. Small-molecule kinase inhibitors that are now approvedfor oncology indications include imatinib, gefitinib, erlotinib,sorafenib, sunitinib and dasatinib [Baselga J., Science, 2006, 312,1175-1178]. A number of kinases such as JAK2, FLT3 and CDK2 arepromising kinase targets for pharmacological intervention in solidtumours, hematological malignancies, myeloproliferative disorders andnon-malignant proliferative disorders like keloids.

The Janus kinases (JAK) are a family of cytoplasmic tyrosine kinasesconsisting of JAK1, JAK2, JAK3 and Tyk2. They play a pivotal role in thesignaling pathways of numerous cytokines, hormones and growth factors[Rawlings J S et al, J. Cell Sci., 2004, 117, 1281-1283]. Theirintracellular substrates include the family of proteins called SignalTransducer and Activator of Transcription (STAT). The JAK-STAT pathways,through the proper actions of the ligands, regulate importantphysiological processes such as immune response to viruses,erythropoiesis, lactation, lipid homeostasis, etc. However,dysfunctional signaling caused by a myriad of factors result inpathophysiological conditions such as allergies, asthma, rheumatoidarthritis, severe combined immune deficiency, hematologicalmalignancies, etc. In particular, mutations in JAK2 have been associatedwith myeloproliferative disorders (including polycythemia vera,essential thrombocythemia and idiopathic myelofibrosis) and a wide rangeof leukemias and lymphomas [Percy M J et al, Hematol. Oncol., 2005, 23,91-93]. Importantly, the myeloproliferative disorders belong to an areaof unmet medical need where some treatment modalities have not beenupdated over the past few decades [Schafer A I, Blood, 2006, 107,4214-4222].

The myeloproliferative disorders (MPDs) belong to a group ofhematological malignancies arising from clonal expansion of mutatedprogenitor stem cells in the bone marrow. The association of one MPD,chronic myeloid leukemia, with the Philadelphia chromosome has been welldocumented. The Philadelphia negative MPDs include EssentialThrombocythemia (ET), Polycythemia Vera (PV) and Chronic IdiopathicMyelofibrosis (MF). No effective treatment is currently available. Therecent discovery that a single acquired somatic mutation in JAK2 appearsresponsible for many of the features of these MPDs promises to impactthe diagnosis and treatment of patients with these disorders and to spuradditional research into the origins of dysregulated cell growth andfunction. Until recently, most MPDs have been considered to be rare ororphan diseases but studies underway suggest a much higher prevalence.

Essential Thrombocythemia is a chronic MPD characterized by an increasednumber of circulating platelets, profound marrow megakaryocytehyperplasia, splenomegaly and a clinical course punctuated byhemorrhagic or thrombotic episodes or both. Current treatment optionsinclude low dose aspirin, or platelet lowering agents such asanagrelide, interferon or hydroxyurea. These treatments have severe sideeffects that compromise the quality of life of patients.

Polycythemia Vera is a chronic progressive MPD characterized by anelevated hematocrit, an increase in the red cell mass, and usually by anelevated leukocyte count, an elevated platelet count and an enlargedspleen. The most common cause of morbidity and mortality is thepredisposition of PV patients to develop life threatening arterial andvenous thromboses. Treatment options include: phlebotomy with low doseaspirin or myelosuppressive therapy options such as hydroxyurea,interferon or anagrelide. Again, these treatments are not ideal due tosevere side effects.

Chronic Idiopathic Myelofibrosis (MF) is a chronic malignanthematological disorder characterized by an enlarged spleen, varyingdegrees of anemia and low platelet counts, red cells in the peripheralblood that resemble tear drops, the appearance of small numbers ofimmature nucleated red cells and white cells in the blood, varyingdegrees of fibrosis of the marrow cavity (myelofibrosis) and thepresence of marrow cells outside the marrow cavity (extramedullaryhematopoiesis or myeloid metaplasia). Current treatment is directed atalleviation of constitutional symptoms, anemia and symptomaticsplenomegaly. Treatment options include hydroxyurea, interferon,thalidomide with prednisone, and allogeneic stem cell transplant. MF hasthe worst prognosis among the Philadelphia negative MPD and representsan area of greatest unmet medical need.

In addition, due to its role in the angiotensin II signaling pathway,JAK2 is also implicated in the etiology of cardiovascular diseases likecongestive heart failure and pulmonary hypertension [Berk B C et al,Circ. Res, 1997, 80, 607-616]. Furthermore, a putative role for JAK2 hasbeen demonstrated in keloid pathogenesis and may constitute a newapproach for keloid management [Lim C P et al, Oncogene, 2006, 25,5416-5425]. Yet another potential application for JAK2 inhibitors liesin the treatment of retinal diseases as JAK2 inhibition was found tooffer protective effects on photoreceptors in a mouse model of retinaldegeneration [Samardzija M et al, FASEB J., 2006, 10, 1096].

A family of Class III receptor tyrosine kinases (RTK), including c-Fms,c-Kit, fms-like receptor tyrosine kinase 3 (FLT3), and platelet-derivedgrowth factor receptors (PDGFRα and β), play an important role in themaintenance, growth and development of hematopoietic andnon-hematopoietic cells. Overexpression and activating mutations ofthese RTKs are known to be involved in the pathophysiology of diversehuman cancers from both solid and hematological origins [Hannah A L,Curr. Mol. Med., 2005, 5, 625-642]. FLT3 mutations were first reportedas internal tandem duplication (FLT3/ITD) of the juxtamembranedomain-coding sequence; subsequently, point mutations, deletions, andinsertions surrounding the D835 coding sequence have been found[Parcells B W et al, Stem Cells, 2006, 24, 1174-1184]. FLT3 mutationsare the most frequent genetic alterations reported in acute myeloidleukemia (AML) and are involved in the signaling pathway of autonomousproliferation and differentiation block in leukemia cells [Tickenbrock Let al, Expert Opin. Emerging Drugs, 2006, 11, 1-13]. Several clinicalstudies have confirmed that FLT3/ITD is strongly associated with a poorprognosis. Because high-dose chemotherapy and stem cell transplantationcannot overcome the adverse effects of FLT3 mutations, the developmentof FLT3 kinase inhibitors could produce a more efficacious therapeuticstrategy for leukemia therapy.

Cyclin-dependent kinases (CDKs) are serine-threonine kinases that playimportant roles in cell cycle control (CDK1, 2, 4 and 6), transcriptioninitiation (CDK7 and 9), and neuronal function (CDK5) [Knockaert M etal, Trends Pharmacol. Sci., 2002, 23, 417-425]. Aberrations in the cellcycle CDKs and their cyclin partners have been observed in varioustumour types, including those of the breast, colon, liver and brain[Shapiro G I, J. Clin. Oncol., 2006, 24, 1770-1783]. It is believed thatthe pharmacological inhibition of CDK1, 2, 4, 6 and/or 9 may provide anew therapeutic option for diverse cancer patients. In particular, thesimultaneous inhibition of CDK1, 2 and 9 has recently been shown toresult in enhanced apoptotic killing of lung cancer (H1299) andosteosarcoma cells (U2OS), compared with inhibition of single CDK alone[Cai D et al, Cancer Res, 2006, 66, 9270-9280].

Accordingly, compounds that are kinase inhibitors have the potential tomeet the need to provide further biologically active compounds thatwould be expected to have useful, improved pharmaceutical properties inthe treatment of kinase related conditions or disorders such as cancerand other proliferative disorders.

SUMMARY OF THE INVENTION

In one aspect the present invention provides a compound of formula (I):

wherein:

R¹ and R² are each independently selected from the group consisting of:H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy,heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy,heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino,sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³, —CONHR³, —NHCOR³,—NHCOOR³, —NHCONHR³, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl,—SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—,R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each ofwhich may be optionally substituted;

each R³, R⁴, and R⁵ is independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each ofwhich may be optionally substituted;

each R⁶ is independently selected from the group consisting of a bond,alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each ofwhich may be optionally substituted;

Z² is independently selected from the group consisting of a bond, O, S,—N(R⁷)—, —N(R⁷)C₁₋₂alkyl-, and —C₁₋₂alkylN(R⁷)—;

each R⁷ is independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl and acyl, each of which may be optionally substituted;

Ar¹ and Ar² are each independently selected from the group consisting ofaryl and heteroaryl, each of which may be optionally substituted;

L is a group of formula:—X¹—Y—X²—

wherein X¹ is attached to Ar¹ and X² is attached to Ar², and wherein X¹,X² and Y are selected such that the group L has between 5 and 15 atomsin the normal chain,

X¹ and X² are each independently a heteroalkyl group containing at leastone oxygen atom in the normal chain,

Y is a group of formula —CR^(a)═CR^(b)— or an optionally substitutedcycloalkyl group,

wherein R^(a) and R^(b) are each independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each ofwhich may be optionally substituted, or

R^(a) and R^(b) may be joined such that when taken together with thecarbon atoms to which they are attached they form a cycloalkenyl orcycloheteroalkenyl group;

or a pharmaceutically acceptable, salt, N-oxide, or prodrug thereof.

As with any group of structurally related compounds which possess aparticular utility, certain embodiments of variables of the compounds ofthe Formula (I), are particularly useful in their end use application.

In certain embodiments Z² is selected from the group consisting of abond, —N(R⁷)— and —S—. In one specific embodiment Z² is —N(R⁷)—. In aneven more specific embodiment Z² is —N(H)—.

Ar¹ and Ar² are each independently selected from the group consisting ofaryl and heteroaryl and may be monocyclic, bicyclic or polycyclicmoieties. In certain embodiments each of Ar¹ and Ar² is a monocyclic orbicyclic moiety. In certain embodiments each of Ar¹ and Ar² are amonocyclic moiety.

In certain embodiments Ar¹ is selected from the group consisting of:

wherein V¹, V², V³ and V⁴ are each independently selected from the groupconsisting of N, and C(R¹⁰);

W is selected from the group consisting of O, S and NR¹⁰;

W¹ and W² are each independently selected from the group consisting of Nand CR¹⁰;

wherein each R¹⁰ is independently selected from the group consisting of:H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy,heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy,heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino,sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³, —CONHR³, —NHCOR³,—NHCOOR³, —NHCONHR³, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl,—SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—,R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each ofwhich may be optionally substituted,

wherein R³, R⁴, R⁵ and R⁶ are as defined above.

In certain embodiments Ar¹ is selected from the group consisting of:

wherein V¹, V², V³, V⁴, W, W¹, W², R³, R⁴, R⁵ and R⁶ are as definedabove.

In certain embodiments Ar¹ is selected from the group consisting of:

wherein each R¹⁰ is independently as defined above,

k is an integer selected from the group consisting of 0, 1, 2, 3, and 4;and

n is an integer selected from the group consisting of 0, 1, and 2.

In yet an even further embodiment Ar¹ is selected from the groupconsisting of:

wherein R¹⁰ is as defined above.

In certain embodiments Ar¹ is selected from the group consisting of:

wherein each R¹⁰ is independently as defined above, and

q is an integer selected from the group consisting of 0, 1 and 2.

In certain embodiments Ar¹ is selected from the group consisting of:

In certain embodiments Ar¹ is selected from the group consisting of:

In certain embodiments Ar² is selected from the group consisting of:

wherein V⁵, V⁶, V⁷ and V⁸ are independently selected from the groupconsisting of N, and C(R¹¹);

wherein each R¹¹ is independently selected from the group consisting of:H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy,heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy,heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino,sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³, —CONHR³, —NHCOR³,—NHCOOR³, —NHCONHR³, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl,—SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—,R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each ofwhich may be optionally substituted.

In certain embodiments Ar² is selected from the group consisting of:

wherein each R¹¹ is independently as defined above

o is an integer selected from the group consisting of 0, 1, 2, 3, and 4;and

p is an integer selected from the group consisting of 0, 1, 2, and 3.

In certain embodiments Ar² is selected from the group consisting of:

wherein each R¹¹ is as defined above.

In an even further embodiment Ar² is selected from the group consistingof:

In one embodiment of the invention the compound is of the formula (II):

or a pharmaceutically acceptable salt or prodrug thereof

wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, k and o are as defined above.

In one embodiment of the invention the compound is of the formula (III):

or a pharmaceutically acceptable salt or prodrug thereof

wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In one embodiment of the invention the compound is of the formula (IV):

or a pharmaceutically acceptable salt or prodrug thereof

wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In one embodiment of the invention the compound is of the formula (V):

or a pharmaceutically acceptable salt or prodrug thereof

wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In one embodiment of the invention the compound is of the formula (VI):

or a pharmaceutically acceptable salt or prodrug thereof

wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In one embodiment of the invention the compound is of the formula (VII):

or a pharmaceutically acceptable salt or prodrug thereof

wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In the compounds of the invention X¹, X² and Y are chosen such thatthere are between 5 and 15 atoms in the normal chain. In one embodimentof the compounds of the invention X¹, X² and Y are chosen such thatthere are between 6 and 15 atoms in the normal chain. In one specificembodiment of the compounds of the invention X¹, X² and Y are chosensuch that there are 7 atoms in the normal chain. In another specificembodiment of the compounds of the invention X¹, X² and Y are chosensuch that there are 8 atoms in the normal chain.

In the compounds of the invention X¹ and X² are each independently aheteroalkyl group containing at least one oxygen atom in the normalchain.

In certain embodiments X¹ is selected from the group consisting of:

(a) —OC₁₋₅alkyl-,

(b) —C₁₋₅alkylO-, and

(c) —C₁₋₅alkylOC₁₋₅alkyl.

In certain embodiments X¹ is selected from the group consisting of:

(a) —OCH₂—

(b) —CH₂O—,

(c) —OCH₂CH₂—,

(d) —CH₂CH₂O—,

(e) —CH₂OCH₂—, and

(f) —CH₂CH₂OCH₂—.

In one specific embodiment X¹ is —OCH₂—. In another specific embodimentX¹ is —CH₂O—. In another specific embodiment X¹ is —OCH₂CH₂—. In anotherspecific embodiment X¹ is —CH₂CH₂O—. In another specific embodiment X¹is —CH₂OCH₂—. In another specific embodiment X¹ is —CH₂CH₂OCH₂—.

In certain embodiments X² is selected from the group consisting of:

(a) —OC₁₋₅alkyl-,

(b) —C₁₋₅alkylO-, and

(c) —C₁₋₅alkylOC₁₋₅alkyl.

In certain embodiments X² is selected from the group consisting of:

(a) —OCH₂—

(b) —CH₂O—,

(c) —OCH₂CH₂—,

(d) —CH₂CH₂O—,

(e) —CH₂OCH₂—, and

(f) —CH₂CH₂OCH₂—.

In one specific embodiment X² is —OCH₂—. In another specific embodimentX¹ is —CH₂O—. In another specific embodiment X² is —OCH₂CH₂—. In anotherspecific embodiment X² is —CH₂CH₂O—. In another specific embodiment X²is —CH₂OCH₂—. In another specific embodiment X² is —CH₂CH₂OCH₂—.

A particularly useful subset of compounds of the invention are selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof;

wherein R¹, R², R¹⁰, R¹¹, k, Y, q and o are as defined above.

In certain embodiments R¹ is selected from the group consisting of H,halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalky, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, arylamino,sulfonylamino, sulfinylamino, COOH, COR³, COOR³, CONHR³, NHCOR³,NHCOOR³, NHCONHR³, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl,and acyl, each of which may be optionally substituted.

In certain embodiments of the invention R¹ is selected from the groupconsisting of H, chloro, bromo, iodo, methyl, ethyl, propyl, butyl,pentyl, hexyl, cyclopropyl, cyclobutyl, phenyl, hydroxy, methoxy,ethoxy, phenoxy, benzyloxy, amino, methylamino, ethylamino, propylamino,butylamino, pentylamino and hexylamino, each of which may be optionallysubstituted.

In certain embodiments R¹ is selected from the group consisting of H,chloro, bromo, iodo, amino, methylamino, ethylamino, propylamino,butylamino, pentylamino and hexylamino, each of which may be optionallysubstituted.

In a specific embodiment R¹ is H.

In certain embodiments R² is selected from the group consisting of H,halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalky, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, arylamino,sulfonylamino, sulfinylamino, COOH, COR³, COOR³, CONHR³, NHCOR³,NHCOOR³, NHCONHR³, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl,and acyl, each of which may be optionally substituted.

In certain embodiments R² is selected from the group consisting of H,chloro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl,cyclopropyl, cyclobutyl, phenyl, hydroxy, methoxy, ethoxy, phenoxy,benzyloxy, amino, methylamino, ethylamino, propylamino, butylamino,pentylamino and hexylamino, each of which may be optionally substituted.

In certain embodiments R² is selected from the group consisting of H,chloro, bromo, iodo, amino, methylamino, ethylamino, propylamino,butylamino, pentylamino and hexylamino, each of which may be optionallysubstituted.

In one specific embodiment R² is selected from the group consisting of Hand alkyl.

In another specific embodiment R² is H or methyl.

In certain embodiments R³ is selected from the group consisting of H,C₁-C₆ alkyl and acyl. In another embodiment R³ is selected from thegroup consisting of H and C₁-C₄ alkyl. In a specific embodiment R³ isC₁-C₄ alkyl.

In certain embodiments R⁴ is selected from the group consisting of H andC₁-C₄ alkyl. In a specific embodiment R⁴ is C₁-C₄ alkyl.

In certain embodiments R⁵ is selected from the group consisting of C₁-C₄alkyl, heteroalkyl and acyl. In a specific embodiment R⁵ is C₁-C₄ alkyl.

In certain embodiments R⁶ is selected from the group consisting of abond, C₁-C₄ alkyl, heteroalkyl and acyl. In specific embodiment R⁶ isC₁-C₄ alkyl or a bond.

In certain embodiments R⁷ is selected from the group consisting of H andC₁-C₄ alkyl. In a specific embodiment R⁷ is H.

In certain embodiments of the compounds of the invention each R¹⁰ isindependently selected from the group consisting of H, halogen, amino,alkyl, haloalkyl, haloalkenyl, heterocycloalkyl, aryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,and alkoxyalkyl, each of which may be optionally substituted.

In certain embodiments each R¹⁰ is independently selected from the groupconsisting of H, hydroxyl, fluoro, amino, methoxy, methyl, ethyl,propyl, butyl, pentyl, hexyl, phenyl, and 2-morpholino-ethoxy, each ofwhich may be optionally substituted.

In certain embodiments each R¹¹ is independently selected from the groupconsisting of H, halogen, alkyl, amino, NR³R⁴, alkylsulfonyl, haloalkyl,heteroalkyl, haloalkenyl, heterocycloalkyl, aryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylsulfonyloxy, arylheteroalkyl, hydroxy,hydroxyalkyl, alkoxy, and alkoxyalkyl, each of which may be optionallysubstituted.

In certain embodiments each R¹¹ is independently selected from the groupconsisting of H, hydroxyl, methoxy, methyl, ethyl, propyl, butyl,pentyl, hexyl, phenyl, and 2-morpholino-ethoxy, each of which may beoptionally substituted.

In certain embodiments of the invention each R¹¹ is independentlyselected from the group consisting of H, alkoxy, heteroalkyl,heterocycloalkyl, heterocycloalkylheteroalkyl and arylsulfonyloxy, eachof which may be optionally substituted.

In certain embodiments of the invention k is 0 or 1. In one embodiment kis 0. In another embodiment k is 1.

In certain embodiments of the invention q is 0 or 1. In one embodiment qis 0. In another embodiment q is 1.

In certain embodiments of the invention o is 0, 1, or 2. In oneembodiment o is one. In another embodiment o is 1. In another embodimento is 2.

In certain embodiments of the invention each R¹¹ is independentlyselected from the group consisting of:

In one embodiment Y is selected from the group consisting of:

In a specific embodiment Y is

In another specific embodiment Y is

In another specific embodiment Y is a cyclopropyl group.

Many if not all of the variables discussed above may be optionallysubstituted. If the variable is optionally substituted then in certainembodiments the optional substituent is selected from the groupconsisting of: halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl,alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy,cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy,heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino,alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, —COOH, —COR⁵,—C(O)OR⁵, —SH, —SR⁵, —OR⁶, and acyl.

In certain embodiments the substituents are selected from the groupconsisting of: halogen, ═O, ═S, —CN, —NO₂, alkyl, alkenyl, heteroalkyl,haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, acylamino,phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl,aminosulfonyl, —C(O)OR⁵, COOH, SH, and acyl.

In addition to compounds of Formula I, the embodiments disclosed arealso directed to pharmaceutically acceptable salts, pharmaceuticallyacceptable N-oxides, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites of such compounds, andpharmaceutically acceptable salts of such metabolites.

The invention also relates to pharmaceutical compositions including acompound of the invention with a pharmaceutically acceptable carrier,diluent or excipient.

In a further aspect the invention provides a method of inhibiting one ormore protein kinase(s) including exposing the one or more proteinkinase(s) and/or co-factor(s) thereof to an effective amount of acompound of the invention. In one embodiment the compound is a compoundof formula (I), (II), (III), (IV), (V), (VI) or (VII).

The compounds disclosed herein may act directly and solely on the kinasemolecule to inhibit biological activity. However, it is understood thatthe compounds may also act at least partially on co-factors that areinvolved in the phosphorylation process. For example, where the kinaseis cyclin-dependent, a co-factor such as cyclinA is involved in thetransfer of phosphate from ATP (also considered a co-factor in itself)to the substrate molecule. Other kinase co-factors include ionic species(such as zinc and calcium), lipids (such as phosphatidylserine), anddiacylglycerols.

In one embodiment of the method the one or more protein kinase(s) is acyclin-dependent protein kinase. In a specific embodiment thecyclin-dependent kinase is a Group I CMCG kinase. In one embodiment theGroup I CMCG kinase is selected from the group consisting of CDC2Hs,CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3,CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRK1, PfC2R, EhC2R, CfCdc2R,cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functionalequivalent thereof. In a specific embodiment the Group I CMCG kinase isCDK2 or a functional equivalent thereof.

In another embodiment of the method the one or more protein kinase(s) isa protein tyrosine kinase. In one form of this embodiment the proteintyrosine kinase is a Group VII protein tyrosine kinase. In oneembodiment the Group VII protein tyrosine kinase is selected from thegroup consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalentthereof. In a specific embodiment the Group VII protein tyrosine kinaseis JAK2 or a functional equivalent thereof. In one form of the method,the JAK2 includes a recurrent unique acquired clonal mutation. Thismutation is observed in a majority of polycythemia vera (PV) patientsand a significant proportion of patients with other myeloproliferativedisorders, including, essential thrombocythemia (ET) and chronicidiopathic myelofibrosis (IMF). In one form of the method the mutationis a valine to phenylalanine substitution at position 617 (V617F). Theincidence of this mutation in PV patients is very high (around 78% ofpatients).

The JAK2 mutation is somatic and occurs at the level of a hematopoieticstem cell. Studies have demonstrated that the mutated JAK2 was found inmyeloid cells, i.e., bone marrow cells, granulocytes, platelets anderythroblasts derived from CD34+ cells, but not in T cells. In addition,mutant JAK2 was found in hematopoietic colonies derived fromhematopoietic progenitor cells. Applicant has demonstrated that kinaseinhibitors described herein are capable of inhibiting the activity ofwild type and mutant JAK2.

In another embodiment of the method the protein tyrosine kinase is aGroup XIV protein tyrosine kinase. In one form of this embodiment theGroup XIV protein tyrosine kinase is selected from the group consistingof PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or afunctional equivalent thereof. In one specific embodiment the Group XIVprotein tyrosine kinase is FLT3 or a functional equivalent thereof. Inanother form of the method, the FLT3 kinase includes a mutation. Thereis substantial experimental and clinical evidence to support thehypothesis that FLT3 mutations are important in the initiation ormaintenance of AML in some patients. Activating mutations of FLT3 resultin constitutive activation of FLT3 tyrosine kinase activity and cantransform factor-dependent hematopoietic cells as evidenced byconversion to factor-independent growth and formation of tumours inimmunodeficient mice. In addition, retroviral transduction of primarymurine bone marrow with an AML patient-derived FLT3 ITD (internal tandemduplication) cDNA results in a lethal myeloproliferative syndrome.Furthermore, retroviral transduction of bone marrow derived frompromyelocytic leukemia/retinoic acid receptor (PML-RAR) transgenic micewith FLT3 ITD results in a marked increase in the incidence of acuteprogranulocytic (APL)-like leukemia in such mice when compared with micethat received a transplant of mock-transduced bone marrow. Applicantshave demonstrated that kinase inhibitors described herein are capable ofinhibiting FLT3 including an ITD where there is a duplication of aminoacids VDFREYEYDH at amino acid position 592-601. In an even morespecific embodiment of the method the FLT3 includes an internal tandemduplication. In an even more specific embodiment the internal tandemduplication is a duplication of amino acids VDFREYEYDH at position592-601.

In one embodiment of the method exposing the one or more proteinkinase(s) to the compound includes administering the compound to amammal containing the one or more protein kinase(s).

In one embodiment the one or more protein kinase(s) include at least twokinases selected from the group consisting of CDK2, FLT3 and JAK2 orfunctional equivalents thereof. In one form of this embodiment the oneor more protein kinase(s) include all three of CDK2, FLT3 and JAK2 orfunctional equivalents thereof.

In an even further aspect the invention provides the use of a compoundof the invention to inhibit one or more protein kinase(s). In oneembodiment the compound is a compound of formula (I), (II), (III), (IV),(V), (VI) or (VII).

In one embodiment the one or more protein kinase(s) is acyclin-dependent protein kinase. In a specific embodiment thecyclin-dependent kinase is a Group I CMCG kinase. In one embodiment theGroup I CMCG kinase is selected from the group consisting of CDC2Hs,CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3,CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRK1, PfC2R, EhC2R, CfCdc2R,cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R and functionalequivalents thereof. In a specific embodiment the Group I CMCG kinase isCDK2 or a functional equivalent thereof.

In another embodiment the one or more protein kinase(s) is a proteintyrosine kinase. In one form of this embodiment the protein tyrosinekinase is a Group VII protein tyrosine kinase. In one embodiment theGroup VII protein tyrosine kinase is selected from the group consistingof TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In aspecific embodiment the Group VII protein tyrosine kinase is JAK2 or afunctional equivalent thereof. In a more specific embodiment the JAK2includes a V to F mutation at position 617.

In another embodiment the protein tyrosine kinase is a Group XIV proteintyrosine kinase. In one form of this embodiment the Group XIV proteintyrosine kinase is selected from the group consisting of PDGFR-b,PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functionalequivalent thereof. In one specific embodiment the Group XIV proteintyrosine kinase is FLT3 or a functional equivalent thereof. In an evenmore specific embodiment FLT3 includes an internal tandem duplication.In an even more specific embodiment the internal tandem duplication is aduplication of amino acids VDFREYEYDH at position 592-601.

In one embodiment the one or more protein kinase(s) include at least twokinases selected from the group consisting of CDK2, FLT3 and JAK2 orfunctional equivalents thereof. In one form of this embodiment the oneor more protein kinase(s) include all three of CDK2, FLT3 and JAK2 orfunctional equivalents thereof.

In an even further aspect the invention provides a method of treating orpreventing a condition in a mammal in which inhibition of one or moreprotein kinase(s) and/or co-factor(s) thereof prevents, inhibits orameliorates a pathology or a symptomology of the condition, the methodincluding administration of a therapeutically effective amount of acompound of the invention. In one embodiment the compound is a compoundof formula (I), (II), (III), (IV), (V), (VI) or (VII).

In one embodiment of the method the one or more protein kinase(s) is acyclin-dependent protein kinase. In a specific embodiment thecyclin-dependent kinase is a Group I CMCG kinase. In one embodiment theGroup I CMCG kinase is selected from the group consisting of CDC2Hs,CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3,CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRK1, PfC2R, EhC2R, CfCdc2R,cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functionalequivalent thereof. In a specific embodiment the Group I CMCG kinase isCDK2 or a functional equivalent thereof. In one embodiment the conditionis selected from the group consisting of prostate cancer,retinoblastoma, malignant neoplasm of breast, malignant tumour of colon,endometrial hyperplasia, osteosarcoma, squamous cell carcinoma,non-small cell lung cancer, melanoma, liver cell carcinoma, malignantneoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroidtumour, adenocarcinoma of the colon, T-cell leukemia, glioma,glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis,astrocytoma, bladder neoplasms, musculoskeletal neoplasms andAlzheimer's Disease.

In another embodiment of the method the one or more protein kinase(s) isa protein tyrosine kinase. In one form of this embodiment the proteintyrosine kinase is a Group VII protein tyrosine kinase. In oneembodiment the Group VII protein tyrosine kinase is selected from thegroup consisting of TYK2, JAK1, JAK2 and HOP or a functional equivalentthereof. In a specific embodiment the Group VII protein tyrosine kinaseis JAK2 or a functional equivalent thereof. In a more specificembodiment the JAK2 includes a V to F mutation at position 617. In oneembodiment the condition is selected from the group consisting ofMyeloproliferative disorders (chronic idiopathic myelofibrosis,polycythemia vera, essential thrombocythemia, chronic myeloid leukemia),myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocyticleukemia, acute erythroblastic leukemia, Hodgkin's disease, B-celllymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, coloncarcinoma, prostate cancer, melanoma, myelodysplastic syndromes,keloids, congestive heart failure, ischemia, thrombosis, cardiachypertrophy, pulmonary hypertension, and retinal degeneration.

In another embodiment of the method the protein tyrosine kinase is aGroup XIV protein tyrosine kinase. In one form of this embodiment theGroup XIV protein tyrosine kinase is selected from the group consistingof PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or afunctional equivalent thereof. In one specific embodiment the Group XIVprotein tyrosine kinase is FLT3 or a functional equivalent thereof. Inan even more specific embodiment FLT3 includes an internal tandemduplication. In an even more specific embodiment the internal tandemduplication is a duplication of amino acids VDFREYEYDH at position592-601. In one embodiment the condition is selected from the groupconsisting of acute myeloid leukemia, acute promyelocytic leukemia,acute lymphocytic leukemia, myelodysplastic syndromes, leukocytosis,juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloidleukemia, acute T-cell leukemia, myeloproliferative disorders, andchronic myelomonocytic leukemia.

In one embodiment the one or more protein kinase(s) include at least twokinases selected from the group consisting of CDK2, FLT3 and JAK2 orfunctional equivalents thereof. In one form of this embodiment the oneor more protein kinase(s) include all three of CDK2, FLT3 and JAK2 orfunctional equivalents thereof.

In an even further aspect the invention provides the use of a compoundof the invention in the preparation of a medicament for treating acondition in an animal in which inhibition of one or more proteinkinase(s) can prevent, inhibit or ameliorate the pathology orsymptomology of the condition. In one embodiment the compound is acompound of formula (I), (II), (III), (IV), (V), (VI) or (VII).

In one embodiment the one or more protein kinase(s) is acyclin-dependent protein kinase. In a specific embodiment thecyclin-dependent kinase is a Group I CMCG kinase. In one embodiment theGroup I CMCG kinase is selected from the group consisting of CDC2Hs,CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3,CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRK1, PfC2R, EhC2R, CfCdc2R,cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R or a functionalequivalent thereof. In a specific embodiment the Group I CMCG kinase isCDK2 or a functional equivalent thereof. In one embodiment the conditionis selected from the group consisting of prostate cancer,retinoblastoma, malignant neoplasm of breast, malignant tumour of colon,endometrial hyperplasia, osteosarcoma, squamous cell carcinoma,non-small cell lung cancer, melanoma, liver cell carcinoma, malignantneoplasm of pancreas, myeloid leukemia, cervical carcinoma, fibroidtumour, adenocarcinoma of the colon, T-cell leukemia, glioma,glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis,astrocytoma, bladder neoplasms, musculoskeletal neoplasms andAlzheimer's Disease.

In another embodiment the one or more protein kinase(s) is a proteintyrosine kinase. In one form of this embodiment the protein tyrosinekinase is a Group VII protein tyrosine kinase. In one embodiment theGroup VII protein tyrosine kinase is selected from the group consistingof TYK2, JAK1, JAK2 and HOP or a functional equivalent thereof. In aspecific embodiment the Group VII protein tyrosine kinase is JAK2 or afunctional equivalent thereof. In a more specific embodiment the JAK2includes a V to F mutation at position 617. In one embodiment thecondition is selected from the group consisting of Myeloproliferativedisorders (chronic idiopathic myelofibrosis, polycythemia vera,essential thrombocythemia, chronic myeloid leukemia), myeloidmetaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia,acute erythroblastic leukemia, Hodgkin's disease, B-cell lymphoma, acuteT-cell leukemia, breast carcinoma, ovarian cancer, colon carcinoma,prostate cancer, melanoma, myelodysplastic syndromes, keloids,congestive heart failure, ischemia, thrombosis, cardiac hypertrophy,pulmonary hypertension, and retinal degeneration.

In another embodiment the protein tyrosine kinase is a Group XIV proteintyrosine kinase. In one form of this embodiment the Group XIV proteintyrosine kinase is selected from the group consisting of PDGFR-b,PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4 or a functionalequivalent thereof. In one specific embodiment the Group XIV proteintyrosine kinase is FLT3 or a functional equivalent thereof. In an evenmore specific embodiment FLT3 includes an internal tandem duplication.In an even more specific embodiment the internal tandem duplication is aduplication of amino acids VDFREYEYDH at position 592-601. In oneembodiment the condition is selected from the group consisting of acutemyeloid leukemia, acute promyelocytic leukemia, acute lymphocyticleukemia, myelodysplastic syndromes, leukocytosis, juvenilemyelomonocytic leukemia, acute B-cell leukemia, chronic myeloidleukemia, acute T-cell leukemia, myeloproliferative disorders, andchronic myelomonocytic leukemia.

In one embodiment the one or more protein kinase(s) include at least twokinases selected from the group consisting of CDK2, FLT3 and JAK2 orfunctional equivalents thereof. In one form of this embodiment the oneor more protein kinase(s) include all three of CDK2, FLT3 and JAK2 orfunctional equivalents thereof.

In an even further aspect the invention provides the use of a compoundof the invention in the preparation of a medicament for the treatment orprevention of a kinase-related disorder. In one embodiment the compoundis a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII).

In one embodiment the kinase-related disorder is a proliferativedisorder. In a specific embodiment the proliferative disorder is electedfrom the group consisting of myeloproliferative disorders (chronicidiopathic myelofibrosis, polycythemia vera, essential thrombocythemia,chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocyticleukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia,acute promyelocytic leukemia, acute lymphocytic leukemia, acuteerythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin'sdisease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma,ovarian cancer, colon carcinoma, prostate cancer, melanoma,myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasmof breast, malignant tumour of colon, endometrial hyperplasia,osteosarcoma, squamous cell carcinoma, non-small cell lung cancer,melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloidleukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of thecolon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovariancancer, restenosis, astrocytoma, bladder neoplasms, and musculoskeletalneoplasms.

In one embodiment the proliferative disorder is a myeloproliferativedisorder. In a specific embodiment the myeloproliferative disorder isselected from the group consisting of polycythemia vera, essentialthrombocythemia and idiopathic myelofibrosis.

In another embodiment the proliferative disorder is cancer. In oneembodiment the cancer is a solid tumour. In one embodiment the solidtumour is a tumour present in or metastasized from an organ or tissueselected from the group consisting of breast, ovary, colon, prostate,endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neuraltissue, lymphatic tissue, blood vessel, bladder and muscle.

In one embodiment the cancer is a hematological cancer. In a specificembodiment the hematological cancer is selected from the groupconsisting of acute myeloid leukemia, acute promyelocytic leukemia,acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis,juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloidleukemia, acute T-cell leukemia, chronic myelomonocytic leukemia,myeloid metaplasia, chronic myelomonocytic leukemia, acuteerythroblastic leukemia, Hodgkin's disease, and B-cell lymphoma.

In another embodiment, the kinase-related disorder is a cardiovasculardisorder. In one embodiment the cardiovascular disorder is selected fromthe group consisting of congestive heart failure, ischemia, thrombosis,cardiac hypertrophy and restenosis.

In one embodiment the kinase-related disorder is a neurodegenerativedisorder. In a specific embodiment the neurodegenerative disorder isAlzheimer's disease.

In an even further aspect the invention provides a method of treating orpreventing a kinase-related disorder including administration of atherapeutically effective amount of a compound of the invention to apatient in need thereof. In one embodiment the compound is a compound offormula (I), (II), (III), (IV), (V), (VI) or (VII).

In one embodiment the kinase-related disorder is a proliferativedisorder. In a specific embodiment the proliferative disorder is electedfrom the group consisting of myeloproliferative disorders (chronicidiopathic myelofibrosis, polycythemia vera, essential thrombocythemia,chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocyticleukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia,acute promyelocytic leukemia, acute lymphocytic leukemia, acuteerythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin'sdisease, B-cell lymphoma, acute T-cell leukemia, breast carcinoma,ovarian cancer, colon carcinoma, prostate cancer, melanoma,myelodysplastic syndromes, keloids, retinoblastoma, malignant neoplasmof breast, malignant tumour of colon, endometrial hyperplasia,osteosarcoma, squamous cell carcinoma, non-small cell lung cancer,melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloidleukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of thecolon, glioma, glioblastoma, oligodendroglioma, lymphoma, ovariancancer, restenosis, astrocytoma, bladder neoplasms, and musculoskeletalneoplasms.

In one embodiment the proliferative disorder is a myeloproliferativedisorder. In a specific embodiment the myeloproliferative disorder isselected from the group consisting of polycythemia vera, essentialthrombocythemia and idiopathic myelofibrosis.

In another embodiment the proliferative disorder is cancer. In oneembodiment the cancer is a solid tumour. In one embodiment the solidtumour is a tumour present in or metastasized from an organ or tissueselected from the group consisting of breast, ovary, colon, prostate,endometrium, bone, skin, lung, liver, pancreas, cervix, brain, neuraltissue, lymphatic tissue, blood vessel, bladder and muscle.

In one embodiment the cancer is a hematological cancer. In a specificembodiment the hematological cancer is selected from the groupconsisting of acute myeloid leukemia, acute promyelocytic leukemia,acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis,juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloidleukemia, acute T-cell leukemia, chronic myelomonocytic leukemia,myeloid metaplasia, chronic myelomonocytic leukemia, acuteerythroblastic leukemia, Hodgkin's disease, and B-cell lymphoma.

In another embodiment, the kinase-related disorder is a cardiovasculardisorder. In one embodiment the cardiovascular disorder is selected fromthe group consisting of congestive heart failure, ischemia, thrombosis,cardiac hypertrophy and restenosis.

In one embodiment the kinase-related disorder is a neurodegenerativedisorder. In a specific embodiment the neurodegenerative disorder isAlzheimer's disease.

The invention also provides a method for inhibiting cell proliferationincluding administration of an effective amount of a compound accordingto formula (I). In one embodiment the compound is a compound of formula(II), (III), (IV), (V), (VI) or (VII).

In an even further aspect the invention provides a method of synthesisof a compound of formula (I) the method including the steps of:

(a) providing a compound of the formula

wherein R¹, R², R^(a), R^(b), Z², Ar¹, Ar², X¹ and X² are as definedabove;

(b) subjecting the compound to ring closing metathesis;

(c) optionally reacting the double bond thus formed to form a cycloalkylgroup.

DETAILED DESCRIPTION OF THE INVENTION

In this specification a number of terms are used which are well known toa skilled addressee. Nevertheless for the purposes of clarity a numberof terms will be defined.

As used herein, the term unsubstituted means that there is nosubstituent or that the only substituents are hydrogen.

The term “optionally substituted” as used throughout the specificationdenotes that the group may or may not be further substituted or fused(so as to form a condensed polycyclic system), with one or morenon-hydrogen substituent groups. In certain embodiments the substituentgroups are one or more groups independently selected from the groupconsisting of halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl,cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl,heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl,alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy,alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy,arylalkyloxy, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino,aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl,alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl,arylsulfinyl, aminosulfinylaminoalkyl, —COOH, —COR⁵, —C(O)OR⁵, CONHR⁵,NHCOR⁵, NHCOOR⁵, NHCONHR⁵, C(═NOH)R⁵, —SH, —SR⁵, —OR⁵, and acyl.

“Alkyl” as a group or part of a group refers to a straight or branchedaliphatic hydrocarbon group, preferably a C₁-C₁₄ alkyl, more preferablyC₁-C₁₀ alkyl, most preferably C₁-C₆ unless otherwise noted. Examples ofsuitable straight and branched C₁-C₆ alkyl substituents include methyl,ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and thelike. The group may be a terminal group or a bridging group.

“Alkylamino” includes both mono-alkylamino and dialkylamino, unlessspecified. “Mono-alkylamino” means a —NH-Alkyl group, in which alkyl isas defined above. “Dialkylamino” means a —N(alkyl)₂ group, in which eachalkyl may be the same or different and are each as defined herein foralkyl. The alkyl group is preferably a C₁-C₆ alkyl group. The group maybe a terminal group or a bridging group.

“Arylamino” includes both mono-arylamino and di-arylamino unlessspecified. Mono-arylamino means a group of formula arylNH—, in whicharyl is as defined herein. di-arylamino means a group of formula(aryl)₂N— where each aryl may be the same or different and are each asdefined herein for aryl. The group may be a terminal group or a bridginggroup.

“Acyl” means an alkyl-CO— group in which the alkyl group is as describedherein. Examples of acyl include acetyl and benzoyl. The alkyl group ispreferably a C₁-C₆ alkyl group. The group may be a terminal group or abridging group.

“Alkenyl” as a group or part of a group denotes an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched preferably having 2-14 carbon atoms, morepreferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in thenormal chain. The group may contain a plurality of double bonds in thenormal chain and the orientation about each is independently E or Z.Exemplary alkenyl groups include, but are not limited to, ethenyl,propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. Thegroup may be a terminal group or a bridging group.

“Alkoxy” refers to an —O-alkyl group in which alkyl is defined herein.Preferably the alkoxy is a C₁-C₆alkoxy. Examples include, but are notlimited to, methoxy and ethoxy. The group may be a terminal group or abridging group.

“Alkenyloxy” refers to an —O— alkenyl group in which alkenyl is asdefined herein. Preferred alkenyloxy groups are C₁-C₆ alkenyloxy groups.The group may be a terminal group or a bridging group.

“Alkynyloxy” refers to an —O-alkynyl group in which alkynyl is asdefined herein. Preferred alkynyloxy groups are C₁-C₆ alkynyloxy groups.The group may be a terminal group or a bridging group.

“Alkoxycarbonyl” refers to an —C(O)—O-alkyl group in which alkyl is asdefined herein. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but not limited to, methoxycarbonyl andethoxycarbonyl. The group may be a terminal group or a bridging group.

“Alkylsulfinyl” means a —S(O)-alkyl group in which alkyl is as definedabove. The alkyl group is preferably a C₁-C₆ alkyl group. Exemplaryalkylsulfinyl groups include, but not limited to, methylsulfinyl andethylsulfinyl. The group may be a terminal group or a bridging group.

“Alkylsulfonyl” refers to a —S(O)₂-alkyl group in which alkyl is asdefined above. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but not limited to methylsulfonyl and ethylsulfonyl.The group may be a terminal group or a bridging group.

“Alkynyl” as a group or part of a group means an aliphatic hydrocarbongroup containing a carbon-carbon triple bond and which may be straightor branched preferably having from 2-14 carbon atoms, more preferably2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.Exemplary structures include, but are not limited to, ethynyl andpropynyl. The group may be a terminal group or a bridging group.

“Alkylaminocarbonyl” refers to an alkylamino-carbonyl group in whichalkylamino is as defined above. The group may be a terminal group or abridging group.

“Cycloalkyl” refers to a saturated or partially saturated, monocyclic orfused or spiro polycyclic, carbocycle preferably containing from 3 to 9carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like, unless otherwise specified. It includesmonocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systemssuch as decalin, and polycyclic systems such as adamantane. The groupmay be a terminal group or a bridging group.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem containing at least one carbon-carbon double bond and preferablyhaving from 5-10 carbon atoms per ring. Exemplary monocycliccycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.The cycloalkenyl group may be substituted by one or more substituentgroups. The group may be a terminal group or a bridging group.

The above discussion of alkyl and cycloalkyl substituents also appliesto the alkyl portions of other substituents, such as without limitation,alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl,alkylsulfonyl and alkyl ester substituents and the like.

“Cycloalkylalkyl” means a cycloalkyl-alkyl-group in which the cycloalkyland alkyl moieties are as previously described. Exemplarymonocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl and cycloheptylmethyl. The group may be a terminalgroup or a bridging group.

“Halogen” represents chlorine, fluorine, bromine or iodine.

“Heterocycloalkyl” refers to a saturated or partially saturatedmonocyclic, bicyclic, or polycyclic ring containing at least oneheteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10membered, more preferably 4 to 7 membered. Examples of suitableheterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl,tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl,morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and1,4-oxathiapane. The group may be a terminal group or a bridging group.

“Heterocycloalkenyl” refers to a heterocycloalkyl as described above butcontaining at least one double bond. The group may be a terminal groupor a bridging group.

“Heterocycloalkylalkyl” refers to a heterocycloalkyl-alkyl group inwhich the heterocycloalkyl and alkyl moieties are as previouslydescribed. Exemplary heterocycloalkylalkyl groups include(2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl. The groupmay be a terminal group or a bridging group.

“Heteroalkyl” refers to a straight- or branched-chain alkyl grouppreferably having from 2 to 14 carbons, more preferably 2 to 10 carbonsin the chain, one or more of which has been replaced by a heteroatomselected from S, O, P and N. Exemplary heteroalkyls include alkylethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, andthe like. The group may be a terminal group or a bridging group. As usedherein reference to the normal chain when used in the context of abridging group refers to the direct chain of atoms linking the twoterminal positions of the bridging group.

“Aryl” as a group or part of a group denotes (i) an optionallysubstituted monocyclic, or fused polycyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) preferably having from5 to 12 atoms per ring. Examples of aryl groups include phenyl,naphthyl, and the like; (ii) an optionally substituted partiallysaturated bicyclic aromatic carbocyclic moiety in which a phenyl and aC₅₋₇ cycloalkyl or C₅₋₇ cycloalkenyl group are fused together to form acyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. Thegroup may be a terminal group or a bridging group.

“Arylalkenyl” means an aryl-alkenyl-group in which the aryl and alkenylare as previously described. Exemplary arylalkenyl groups includephenylallyl. The group may be a terminal group or a bridging group.

“Arylalkyl” means an aryl-alkyl-group in which the aryl and alkylmoieties are as previously described. Preferred arylalkyl groups containa C₁₋₅ alkyl moiety. Exemplary arylalkyl groups include benzyl,phenethyl and naphthelenemethyl. The group may be a terminal group or abridging group.

“Heteroaryl” either alone or part of a group refers to groups containingan aromatic ring (preferably a 5 or 6 membered aromatic ring) having oneor more heteroatoms as ring atoms in the aromatic ring with theremainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude nitrogen, oxygen and sulphur. Examples of heteroaryl includethiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan,isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole,1H-indazole, purine, quinoline, isoquinoline, phthalazine,naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine,acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole,isooxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-,or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl 1-, 2-, or 3-indolyl, and2-, or 3-thienyl. The group may be a terminal group or a bridging group.

“Heteroarylalkyl” means a heteroaryl-alkyl group in which the heteroaryland alkyl moieties are as previously described. Preferredheteroarylalkyl groups contain a lower alkyl moiety. Exemplaryheteroarylalkyl groups include pyridylmethyl. The group may be aterminal group or a bridging group.

“Lower alkyl” as a group means unless otherwise specified, an aliphatichydrocarbon group which may be straight or branched having 1 to 6 carbonatoms in the chain, more preferably 1 to 4 carbons such as methyl,ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl ortertiary-butyl). The group may be a terminal group or a bridging group.

It is understood that included in the family of compounds of Formula (I)are isomeric forms including diastereoisomers, enantiomers, tautomers,and geometrical isomers in “E” or “Z” configurational isomer or amixture of E and Z isomers. It is also understood that some isomericforms such as diastereomers, enantiomers, and geometrical isomers can beseparated by physical and/or chemical methods and by those skilled inthe art.

Some of the compounds of the disclosed embodiments may exist as singlestereoisomers, racemates, and/or mixtures of enantiomers and/ordiastereomers. All such single stereoisomers, racemates and mixturesthereof, are intended to be within the scope of the subject matterdescribed and claimed.

Additionally, Formula (I) is intended to cover, where applicable,solvated as well as unsolvated forms of the compounds. Thus, eachformula includes compounds having the indicated structure, including thehydrated as well as the non-hydrated forms.

In addition to compounds of the Formula (I), the compounds of thevarious embodiments include pharmaceutically acceptable salts, prodrugs,N-oxides and active metabolites of such compounds, and pharmaceuticallyacceptable salts of such metabolites.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the above-identified compounds, andinclude pharmaceutically acceptable acid addition salts and baseaddition salts. Suitable pharmaceutically acceptable acid addition saltsof compounds of Formula (I) may be prepared from an inorganic acid orfrom an organic acid. Examples of such inorganic acids are hydrochloric,sulfuric, and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic andsulfonic classes of organic acids, examples of which are formic, acetic,propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Suitablepharmaceutically acceptable base addition salts of compounds of Formula(I) include metallic salts made from lithium, sodium, potassium,magnesium, calcium, aluminium, and zinc, and organic salts made fromorganic bases such as choline, diethanolamine, morpholine. Otherexamples of organic salts are: ammonium salts, quaternary salts such astetramethylammonium salt; amino acid addition salts such as salts withglycine and arginine. Additional information on pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,19th Edition, Mack Publishing Co., Easton, Pa. 1995. In the case ofagents that are solids, it is understood by those skilled in the artthat the inventive compounds, agents and salts may exist in differentcrystalline or polymorphic forms, all of which are intended to be withinthe scope of the present invention and specified formulae.

“Prodrug” means a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis, reduction or oxidation) to a compound offormula (I). For example an ester prodrug of a compound of formula (I)containing a hydroxyl group may be convertible by hydrolysis in vivo tothe parent molecule. Suitable esters of compounds of formula (I)containing a hydroxyl group, are for example acetates, citrates,lactates, tartrates, malonates, oxalates, salicylates, propionates,succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates,gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates,ethanesulphonates, benzenesulphonates, p-toluenesulphonates,cyclohexylsulphamates and quinates. As another example an ester prodrugof a compound of formula (I) containing a carboxy group may beconvertible by hydrolysis in vivo to the parent molecule. (Examples ofester prodrugs are those described by F. J. Leinweber, Drug Metab. Res.,18:379, 1987).

The term “therapeutically effective amount” or “effective amount” is anamount sufficient to effect beneficial or desired clinical results. Aneffective amount can be administered in one or more administrations. Aneffective amount is typically sufficient to palliate, ameliorate,stabilize, reverse, slow or delay the progression of the disease state.

The term “normal chain” refers to the direct chain joining the two endsof a linking moiety. In reference to the present compounds analkoxyalkyl group is a heteroalkyl group containing a heteroatom in thenormal chain (in this case an oxygen atom). An amide group is also aheteroalkyl group but it does not contain an oxygen atom in the normalchain (it has a nitrogen atom in the normal chain).

The term “functional equivalent” is intended to include variants of thespecific protein kinase species described herein. It will be understoodthat kinases may have isoforms, such that while the primary, secondary,tertiary or quaternary structure of a given kinase isoform is differentto the protoypical kinase, the molecule maintains biological activity asa protein kinase. Isoforms may arise from normal allelic variationwithin a population and include mutations such as amino acidsubstitution, deletion, addition, truncation, or duplication. Alsoincluded within the term “functional equivalent” are variants generatedat the level of transcription. Many kinases (including JAK2 and CDK2)have isoforms that arise from transcript variation. It is also knownthat FLT3 has an isoform that is the result of exon-skipping. Otherfunctional equivalents include kinases having altered post-translationalmodification such as glycosylation.

Specific compounds of the invention include the following:

The compounds of the invention have the ability to inhibit the activityof certain protein kinases. The ability to inhibit kinase activity maybe a result of the compounds of the invention acting directly and solelyon the kinase molecule to inhibit biological activity. However, it isunderstood that the compounds may also act at least partially onco-factors of the kinase in question that are involved in thephosphorylation process. For example, where the kinase iscyclin-dependent, a co-factor such as cyclinA is involved in thetransfer of phosphate from ATP (also considered a co-factor in itself)to the substrate molecule. Other kinase co-factors include ionic species(such as zinc and calcium), lipids (such as phosphatidylserine), anddiacylglycerols.

The compounds may have activity against a wide range of protein kinases.One suitable family of protein kinases are the cyclin-dependent proteinkinases. An example of the cyclin-dependent kinases is the Group I CMCGkinases. Examples of Group I CMCG kinases include CDC2Hs, CDK2, CDK3,CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2,Dm2c, Ddcdc2, DdPRK, LmmCRK1, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28,PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R. A Group I CMCG kinase ofparticular interest is CDK2.

Another family of protein kinases are protein tyrosine kinases. Anexample of protein tyrosine kinases is a Group VII protein tyrosinekinase. Examples of Group VII protein tyrosine kinase include TYK2,JAK1, JAK2 and HOP. A protein kinase of particular interest is the GroupVII protein tyrosine kinase is JAK2. The JAK2 protein kinase may includea recurrent unique acquired clonal mutation. As stated previously thismutation is observed in a majority of polycythemia vera (PV) patientsand a significant proportion of patients with other myeloproliferativedisorders, including, essential thrombocythemia (ET) and chronicidiopathic myelofibrosis (IMF). A typical mutation is a valine tophenylalanine substitution at position 617 (V617F). The incidence ofthis mutation in PV patients is very high (around 78% of patients).

Another example of protein tyrosine kinases is the Group XIV proteintyrosine kinases. Examples of the Group XIV protein tyrosine kinaseinclude PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4.A Group XIV protein tyrosine kinase of particular interest is FLT3. TheFLT3 kinase may include a mutation. There is substantial experimentaland clinical evidence to support the hypothesis that FLT3 mutations areimportant in the initiation or maintenance of AML in some patients.Activating mutations of FLT3 result in constitutive activation of FLT3tyrosine kinase activity and can transform factor-dependenthematopoietic cells as evidenced by conversion to factor-independentgrowth and formation of tumours in immunodeficient mice. In addition,retroviral transduction of primary murine bone marrow with an AMLpatient-derived FLT3 ITD (internal tandem duplication) cDNA results in alethal myeloproliferative syndrome. Furthermore, retroviral transductionof bone marrow derived from promyelocytic leukemia/retinoic acidreceptor (PML-RAR) transgenic mice with FLT3 ITD results in a markedincrease in the incidence of acute progranulocytic (APL)-like leukemiain such mice when compared with mice that received a transplant ofmock-transduced bone marrow. Applicants have demonstrated that kinaseinhibitors described herein are capable of inhibiting FLT3 including anITD where there is a duplication of amino acids VDFREYEYDH at amino acidposition 592-601. In an even more specific embodiment of the method theFLT3 includes an internal tandem duplication. In an even more specificembodiment the internal tandem duplication is a duplication of aminoacids VDFREYEYDH at position 592-601.

The inhibition of the protein kinase may be carried out in any of anumber of well known ways in the art. For example if inhibition of theprotein kinase in vitro is desired an appropriate amount of the compoundof the invention may be added to a solution containing the kinase. Incircumstances where it is desired to inhibit the activity of the kinasein a mammal the inhibition of the kinase typically involvesadministering the compound to a mammal containing the kinase.

Accordingly the compounds of the invention may find a multiple number ofapplications in which their ability to inhibit protein kinases of thetype mentioned above can be utilised. For example the compounds may beused to inhibit protein kinases. The compounds may also be used intreating or preventing a condition in a mammal in which inhibition of aprotein kinase and/or co-factor thereof prevents, inhibits orameliorates a pathology or a symptomology of the condition.

Examples of conditions that may be treated by inhibition of proteinkinases include prostate cancer, retinoblastoma, malignant neoplasm ofbreast, malignant tumour of colon, endometrial hyperplasia,osteosarcoma, squamous cell carcinoma, non-small cell lung cancer,melanoma, liver cell carcinoma, malignant neoplasm of pancreas, myeloidleukemia, cervical carcinoma, fibroid tumour, adenocarcinoma of thecolon, T-cell leukemia, glioma, glioblastoma, oligodendroglioma,lymphoma, ovarian cancer, restenosis, astrocytoma, bladder neoplasms,musculoskeletal neoplasms and Alzheimer's Disease.

Other conditions that may be treated by inhibition of protein kinasesinclude conditions such as Myeloproliferative disorders (chronicidiopathic myelofibrosis, polycythemia vera, essential thrombocythemia,chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocyticleukemia, acute lymphocytic leukemia, acute erythroblastic leukemia,Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breastcarcinoma, ovarian cancer, colon carcinoma, prostate cancer, melanoma,myelodysplastic syndromes, keloids, congestive heart failure, ischemia,thrombosis, cardiac hypertrophy, pulmonary hypertension, and retinaldegeneration.

Other conditions that may be treated by inhibition of protein kinasesinclude acute myeloid leukemia, acute promyelocytic leukemia, acutelymphocytic leukemia, myelodysplastic syndromes, leukocytosis, juvenilemyelomonocytic leukemia, acute B-cell leukemia, chronic myeloidleukemia, acute T-cell leukemia, myeloproliferative disorders, andchronic myelomonocytic leukemia.

The compounds of the invention may also be used the preparation of amedicament for treating a condition in an animal in which inhibition ofa protein kinase can prevent, inhibit or ameliorate the pathology orsymptomology of the condition. The compounds of the invention may alsobe used in the preparation of a medicament for the treatment orprevention of a kinase-related disorder.

One example of a kinase-related disorder is a proliferative disorder. Ina specific embodiment the proliferative disorder is elected from thegroup consisting of myeloproliferative disorders (chronic idiopathicmyelofibrosis, polycythemia vera, essential thrombocythemia, chronicmyeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia,acute myeloid leukemia, juvenile myelomonocytic leukemia, acutepromyelocytic leukemia, acute lymphocytic leukemia, acute erythroblasticleukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-celllymphoma, acute T-cell leukemia, breast carcinoma, ovarian cancer, coloncarcinoma, prostate cancer, melanoma, myelodysplastic syndromes,keloids, retinoblastoma, malignant neoplasm of breast, malignant tumourof colon, endometrial hyperplasia, osteosarcoma, squamous cellcarcinoma, non-small cell lung cancer, melanoma, liver cell carcinoma,malignant neoplasm of pancreas, myeloid leukemia, cervical carcinoma,fibroid tumour, adenocarcinoma of the colon, glioma, glioblastoma,oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma,bladder neoplasms, and musculoskeletal neoplasms.

One example of a proliferative disorder is cancer. The cancer may be asolid tumour. The solid tumour may be a tumour present in ormetastasized from an organ or tissue selected from the group consistingof breast, ovary, colon, prostate, endometrium, bone, skin, lung, liver,pancreas, cervix, brain, neural tissue, lymphatic tissue, blood vessel,bladder and muscle.

Another example of a cancer is a hematological cancer. Examples ofhematological cancers include acute myeloid leukemia, acutepromyelocytic leukemia, acute lymphocytic leukemia, myelodysplasticsyndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B-cellleukemia, chronic myeloid leukemia, acute T-cell leukemia, chronicmyelomonocytic leukemia, myeloid metaplasia, chronic myelomonocyticleukemia, acute erythroblastic leukemia, Hodgkin's disease, and B-celllymphoma.

Another kinase-related disorder is a cardiovascular disorder. Examplesof cardiovascular disorder include congestive heart failure, ischemia,thrombosis, cardiac hypertrophy and restenosis.

Another kinase-related disorder is a neurodegenerative disorder. Theneurodegenerative disorder may be Alzheimer's disease.

The compounds disclosed have the ability to be used in the treatment ofproliferative disorders. An example of such a disorder is cancer.

Administration of compounds within Formula (I) to humans can be by anyof the accepted modes for enteral administration such as oral or rectal,or by parenteral administration such as subcutaneous, intramuscular,intravenous and intradermal routes. Injection can be bolus or viaconstant or intermittent infusion. The active compound is typicallyincluded in a pharmaceutically acceptable carrier or diluent and in anamount sufficient to deliver to the patient a therapeutically effectivedose. In various embodiments the inhibitor compound may be selectivelytoxic or more toxic to rapidly proliferating cells, e.g. canceroustumours, than to normal cells.

As used herein the term ‘cancer’ is a general term intended to encompassthe vast number of conditions that are characterised by uncontrolledabnormal growth of cells.

It is anticipated that the compounds of the invention will be useful intreating various cancers including but not limited to bone cancersincluding Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like,brain and CNS tumours including acoustic neuroma, neuroblastomas, gliomaand other brain tumours, spinal cord tumours, breast cancers, colorectalcancers, advanced colorectal adenocarcinomas, endocrine cancersincluding adrenocortical carcinoma, pancreatic cancer, pituitary cancer,thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrineneoplasma, gastrointestinal cancers including stomach cancer,oesophageal cancer, small intestine cancer, Liver cancer, extra hepaticbile duct cancer, gastrointestinal carcinoid tumour, gall bladdercancer, genitourinary cancers including testicular cancer, penilecancer, prostrate cancer, gynaecological cancers including cervicalcancer, ovarian cancer, vaginal cancer, uterus/endometrium cancer, vulvacancer, gestational trophoblastic cancer, fallopian tube cancer, uterinesarcoma, head and neck cancers including oral cavity cancer, lip cancer,salivary gland cancer, larynx cancer, hypopharynx cancer, orthopharynxcancer, nasal cancer, paranasal cancer, nasopharynx cancer, leukemiasincluding childhood leukemia, acute lymphocytic leukemia, acute myeloidleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, acute promyelocytic leukemia, plasma cell leukemia,myelomas, hematological disorders including myelodysplastic syndromes,myeloproliferative disorders, aplastic anaemia, Fanconi anaemia,Waldenstroms Macroglobulinemia, lung cancers including small cell lungcancer, non-small cell lung cancer, lymphomas including Hodgkin'sdisease, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, peripheralT-cell lymphoma, B-cell lymphoma, Burkitt's lymphoma, AIDS relatedLymphoma, eye cancers including retinoblastoma, intraocular melanoma,skin cancers including melanoma, non-melanoma skin cancer, merkel cellcancer, soft tissue sarcomas such as childhood soft tissue sarcoma,adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancersincluding kidney cancer, Wilms tumour, bladder cancer, urethral cancer,and transitional cell cancer. Exemplary cancers that may be treated bycompounds of this invention include Hematologic cancer such asmyeloproliferative disorders (idiopathic myelofibrosis, polycythemiavera, essential thrombocythemia, chronic myeloid leukemia), myeloidmetaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia,acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease,B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes,plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma;gynaecologic cancer such as breast carcinoma, ovarian cancer, cervicalcancer, vaginal and vulva cancer, endometrial hyperplasia;gastrointestinal tract cancer such as colorectal carcinoma, polyps,liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer;urinary tract cancer such as prostate cancer, kidney and renal cancer;urinary bladder cancer, urethral cancer, penile cancer; skin cancer suchas melanoma; brain tumour such as glioblastoma, neuroblastoma,astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma,menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such asnasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancersuch as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease suchas retinoblastoma; musculo-skeleton diseases such as osteosarcoma,musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid tumour.

Exemplary cancers that may be treated by compounds of this inventioninclude but are not limited to bladder cancer, breast cancer, cervicalcancer, colorectal cancer, colon cancer, gastric cancer, neuroblastoma,retinoblastoma, ovarian cancer, pancreatic cancer, leukemia, lymphoma,prostate cancer and lung cancer.

Exemplary cancers that may be treated by compounds of this invention arecolon cancer, colorectal cancer, pancreatic cancer and cervical cancer.

Even further exemplary cancers that may be treated by compounds of thepresent inventions include but are not limited to B-cell lymphoma (e.g.Burkitt's lymphoma), leukemia (e.g. acute promyelocytic leukemia,erythroleukemia), cutaneous T-cell lymphoma (CTCL) and peripheral T-celllymphoma.

Even further exemplary cancers that may be treated by compounds of thepresent invention include solid tumours and hematologic malignancies.

It is anticipated that, by virtue of their JAK2 inhibition, thecompounds of the invention will also be useful in treating variousmyeloproliferative disorders which may include polycythemia vera,essential thrombocythemia and idiopathic myelofibrosis.

In using the compounds of the invention they can be administered in anyform or mode which makes the compound bioavailable. One skilled in theart of preparing formulations can readily select the proper form andmode of administration depending upon the particular characteristics ofthe compound selected, the condition to be treated, the stage of thecondition to be treated and other relevant circumstances. We refer thereader to Remingtons Pharmaceutical Sciences, 19^(th) edition, MackPublishing Co. (1995) for further information.

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition in combination with apharmaceutically acceptable carrier, diluent or excipient. The compoundsof the invention, while effective themselves, are typically formulatedand administered in the form of their pharmaceutically acceptable saltsas these forms are typically more stable, more easily crystallised andhave increased solubility.

The compounds are, however, typically used in the form of pharmaceuticalcompositions which are formulated depending on the desired mode ofadministration. As such in a further embodiment the present inventionprovides a pharmaceutical composition including a compound of Formula(I) and a pharmaceutically acceptable carrier, diluent or excipient. Thecompositions are prepared in manners well known in the art.

The invention in other embodiments provides a pharmaceutical pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. In sucha pack or kit can be found a container having a unit dosage of theagent(s). The kits can include a composition comprising an effectiveagent either as concentrates (including lyophilized compositions), whichcan be diluted further prior to use or they can be provided at theconcentration of use, where the vials may include one or more dosages.Conveniently, in the kits, single dosages can be provided in sterilevials so that the physician can employ the vials directly, where thevials will have the desired amount and concentration of agent(s).Associated with such container(s) can be various written materials suchas instructions for use, or a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

The compounds of the invention may be used or administered incombination with one or more additional drug(s) that are anti-cancerdrugs and/or procedures (e.g. surgery, radiotherapy) for the treatmentof the disorder/diseases mentioned. The components can be administeredin the same formulation or in separate formulations. If administered inseparate formulations the compounds of the invention may be administeredsequentially or simultaneously with the other drug(s).

In addition to being able to be administered in combination with one ormore additional drugs that include anti-cancer drugs, the compounds ofthe invention may be used in a combination therapy. When this is donethe compounds are typically administered in combination with each other.Thus one or more of the compounds of the invention may be administeredeither simultaneously (as a combined preparation) or sequentially inorder to achieve a desired effect. This is especially desirable wherethe therapeutic profile of each compound is different such that thecombined effect of the two drugs provides an improved therapeuticresult.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of micro-organisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents that delay absorptionsuch as aluminium monostearate and gelatin.

If desired, and for more effective distribution, the compounds can beincorporated into slow release or targeted delivery systems such aspolymer matrices, liposomes, and microspheres.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

If desired, and for more effective distribution, the compounds can beincorporated into slow release or targeted delivery systems such aspolymer matrices, liposomes, and microspheres.

The active compounds can also be in microencapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Dosage forms for topical administration of a compound of this inventioninclude powders, patches, sprays, ointments and inhalants. The activecompound is mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers, or propellantswhich may be required.

The amount of compound administered will preferably treat and reduce oralleviate the condition. A therapeutically effective amount can bereadily determined by an attending diagnostician by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount a number of factors are to be considered including but notlimited to, the species of animal, its size, age and general health, thespecific condition involved, the severity of the condition, the responseof the patient to treatment, the particular compound administered, themode of administration, the bioavailability of the preparationadministered, the dose regime selected, the use of other medications andother relevant circumstances.

A preferred dosage will be a range from about 0.01 to 300 mg perkilogram of body weight per day. A more preferred dosage will be in therange from 0.1 to 100 mg per kilogram of body weight per day, morepreferably from 0.2 to 80 mg per kilogram of body weight per day, evenmore preferably 0.2 to 50 mg per kilogram of body weight per day. Asuitable dose can be administered in multiple sub-doses per day.

As discussed above, the compounds of the embodiments may be useful fortreating proliferative diseases. Examples of such cell proliferativediseases or conditions include cancer (include any metastases),psoriasis, and smooth muscle cell proliferative disorders such asrestenosis. The inventive compounds may be particularly useful fortreating tumours such as breast cancer, colon cancer, lung cancer,ovarian cancer, prostate cancer, head and/or neck cancer, or renal,gastric, pancreatic cancer and brain cancer as well as hematologicmalignancies such as lymphoma and leukemia. In addition, the inventivecompounds may be useful for treating a proliferative disease that isrefractory to the treatment with other anti-cancer drugs; and fortreating hyperproliferative conditions such as leukemias, psoriasis andrestenosis. In other embodiments, compounds of this invention can beused to treat pre-cancer conditions or hyperplasia including familialadenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia,endometrial dysplasia, endometrial hyperplasia with atypia, cervicaldysplasia, vaginal intraepithelial neoplasia, benign prostatichyperplasia, papillomas of the larynx, actinic and solar keratosis,seborrheic keratosis and keratoacanthoma.

Synthesis of Pyrimidine Macrocycles

As discussed above the invention provides a method of synthesis of acompound of formula (I) the method including the steps of:

(a) providing a compound of the formula

wherein R¹, R², R^(a), R^(b), Z², Ar¹, Ar², X¹ and X² are as definedabove;

(b) subjecting the compound to ring closing metathesis;

(c) optionally reacting the double bond thus formed to form a cycloalkylgroup.

The methods of the invention involve cyclisation of a diene compound ofthe formula described above which can be produced using procedures wellknown in the art or by the ones detailed below. The exact choice ofmethod used to produce the diene for cyclisation will depend upon thediene selected and methods of synthesis of the dienes are within theskill of the skilled addressee. The compound may be reacted in its freeform although it is typical that it is first converted to a suitableacid salt. Acid salts are well known as is discussed above with thehydrochloride salt and the trifluoroacetic acid salt being found to beparticularly suitable.

Once the diene of an appropriate formula has been provided as discussedabove it is then subjected to ring closing metathesis using standardconditions. A number of catalysts are well known to be suitable for ringclosing metathesis including a number of ruthenium based catalysts.Suitable ruthenium based catalysts include well-known ruthenium basedcatalysts used in olefin metathesis reactions, such as Grubb's catalyst(first and second generation), Hoveyda's catalyst (first and secondgeneration) and Nolan's catalyst. In each instance it may be necessaryto make appropriate adjustments to the reaction conditions to allowring-closing to occur. In one specific embodiment the catalyst isGrubb's second generation catalyst.

Ruthenium-based catalysts useful for the metathesis cyclisation step, asdiscussed above are all known catalysts that may be obtained by knownsynthetic techniques. For example, see the following references forexamples of suitable ruthenium-based catalysts:

-   Organometallics 2002, 21, 671; 1999, 18, 5416; and 1998, 17, 2758;-   J. Am. Chem. Soc. 2001, 123, 6543; 1999, 121, 791; 1999, 121, 2674;    2002, 124, 4954; 1998, 120, 2484; 1997, 119, 3887; 1996, 118, 100;    and 1996, 118, 9606-   J. Org. Chem. 1998, 63, 9904; and 1999, 64, 7202;-   Angew. Chem. Int. Ed. Engl. 1998, 37, 2685; 1995, 34, 2038; 2000,    39, 3012 and 2002, 41, 4038;-   U.S. Pat. Nos. 5,811,515; 6,306,987 B1; and 6,608,027 B1.

The ratio of diene to catalyst may vary widely as would be clear to askilled addressee in the art. Nevertheless a suitable ratio is such thatthe ratio is from 100:1 to 1:1. A particularly suitable ratio is from20:1 to 2:1. A more specific ratio is from 20:1 to 10:1.

The ring closing metathesis step may be carried out over a broadtemperature range with the range of temperatures typically being chosenbased upon the diene being cyclised, the time of reaction, and thecatalyst chosen. In one embodiment the reaction is carried out at atemperature of from 20 to 200° C. In another embodiment the temperatureis from 30 to 120° C. In another embodiment the temperature is in therange of from 30 to 50° C. In a specific embodiment the temperature is40° C.

The ring-closing step may be carried out in the presence of any suitablenon-interfering solvent that does not interfere with the reaction. Askilled addressee in the area can readily select suitable solvents thatdo not interfere with the reaction, nevertheless, examples of suitablesolvents include alkanes, such as n-pentane, n-hexane or n-heptane,aromatic hydrocarbons, such as benzene, toluene or xylene, chlorinatedhydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane or dichloroethane, ether solvents, such astetrahydrofuran, 2-methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran,cyclopentyl methyl ether, methyl tert-butyl ether, dimethyl ether,diethyl ether or dioxane and methyl alcohol. An example of a specificsolvent is dichloromethane.

The ring closing metathesis step may be carried out over a wide range ofdiene dilutions in the solvent with the ratio of diene to diluenttypically being in the range of from 1:4000 by weight to 1:25 by weight.In another embodiment the ratio is from 1:200 by weight to 1:50 byweight.

The cycloalkylation step may be carried out using any cycloalkylationagent well known in the art. An example of a suitable cycloalkylationagent is a cyclopropanation agent. Examples of cyclopropanation agentsare well known in the art and include diazomethane and carbenes. The useof these agents are well known and it is within the scope of a skilledaddressee to be able to carry out reactions of this type.

The cycloalkylation reactions are typically carried out in anon-interfering solvent such as acetonitrile, ethyl acetate/hexaneadmixtures, ethyl acetate, tetrahydrofuran, ether, toluene, acetone,carbon tetrachloride, and dichloromethane or mixtures thereof. It willbe appreciated by those skilled in the art that a range of solventswould in fact be suitable for use in conducting the reaction of theinvention. In any specific case an optimum solvent can be identified bytrial and experiment using the above solvents and others.

The agents of the various embodiments may be prepared using the reactionroutes and synthesis schemes as described below, employing thetechniques available in the art using starting materials that arereadily available. The preparation of particular compounds of theembodiments is described in detail in the following examples, but theartisan will recognize that the chemical reactions described may bereadily adapted to prepare a number of other agents of the variousembodiments. For example, the synthesis of non-exemplified compounds maybe successfully performed by modifications apparent to those skilled inthe art, e.g. by appropriately protecting interfering groups, bychanging to other suitable reagents known in the art, or by makingroutine modifications of reaction conditions. A list of suitableprotecting groups in organic synthesis can be found in T. W. Greene'sProtective Groups in Organic Synthesis, 3^(rd), John Wiley & Sons, 1991.Alternatively, other reactions disclosed herein or known in the art willbe recognized as having applicability for preparing other compounds ofthe various embodiments.

Reagents useful for synthesizing compounds may be obtained or preparedaccording to techniques known in the art.

In the examples described below, unless otherwise indicated, alltemperatures in the following description are in degrees Celsius and allparts and percentages are by weight, unless indicated otherwise.

Various starting materials and other reagents were purchased fromcommercial suppliers, such as Aldrich Chemical Company or LancasterSynthesis Ltd., and used without further purification, unless otherwiseindicated. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) werepurchased from Aldrich in SureSeal bottles and used as received. Allsolvents were purified by using standard methods in the art, unlessotherwise indicated.

The reactions set forth below were performed under a positive pressureof nitrogen, argon or with a drying tube, at ambient temperature (unlessotherwise stated), in anhydrous solvents, and the reaction flasks arefitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven-dried and/or heat-dried. Analyticalthin-layer chromatography was performed on glass-backed silica gel 60 F254 plates (E Merck (0.25 mm)) and eluted with the appropriate solventratios (v/v). The reactions were assayed by TLC and terminated as judgedby the consumption of starting material.

The TLC plates were visualized by UV absorption or with a p-anisaldehydespray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20 wt% in ethanol) which was activated with heat, or by staining in an iodinechamber. Work-ups were typically done by doubling the reaction volumewith the reaction solvent or extraction solvent and then washing withthe indicated aqueous solutions using 25% by volume of the extractionvolume (unless otherwise indicated). Product solutions were dried overanhydrous sodium sulfate prior to filtration, and evaporation of thesolvents was under reduced pressure on a rotary evaporator and noted assolvents removed in vacuo. Flash column chromatography [Still et al, J.Org. Chem., 43, 2923 (1978)] was conducted using E Merck-grade flashsilica gel (47-61 mm) and a silica gel:crude material ratio of about20:1 to 50:1, unless otherwise stated. Hydrogenolysis was done at thepressure indicated or at ambient pressure.

¹H NMR spectra were recorded on a Bruker instrument operating at 400MHz, and ¹³C-NMR spectra was recorded operating at 100 MHz. NMR spectraare obtained as CDCl₃ solutions (reported in ppm), using chloroform asthe reference standard (7.27 ppm and 77.00 ppm) or CD₃OD (3.4 and 4.8ppm and 49.3 ppm), or an internal tetramethylsilane standard (0.00 ppm)when appropriate. Other NMR solvents were used as needed. When peakmultiplicities are reported, the following abbreviations are used:s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doubletof doublets, dt=doublet of triplets. Coupling constants, when given, arereported in Hertz.

Mass spectra were obtained using LC/MS either in ESI or APCI. Allmelting points are uncorrected.

All final products had greater than 90% purity (by HPLC at wavelengthsof 220 nm and 254 nm).

The following examples are intended to illustrate the embodimentsdisclosed and are not to be construed as being limitations thereto.Additional compounds, other than those described below, may be preparedusing the following described reaction scheme or appropriate variationsor modifications thereof.

General Synthetic Scheme

Scheme 1 is a general synthetic scheme outlining the procedures for themanufacture of compounds of the invention of general formula (VIIIa) and(IXa) being compounds of the invention wherein X¹ and X² are heteroalkylgroups containing at least one oxygen atom in the normal chain, and Ar¹and Ar² are phenylene. This general procedure can be modified to produceother compounds of the invention with different values for X¹, X², Ar¹and Ar² by appropriate modification of the reagents and startingmaterials used. A skilled addressee would readily be able to make thesechanges. The compounds of formula (VIIIa) may be reacted withappropriate reagents to produce the associated cyclopropyl analogs offormula (IXa).

As can be seen in scheme 1 an appropriately substituted2,4-dichloropyrimidine (Ia) is treated under Suzuki coupling conditionswith a suitably functionalized boronic acids of type (IIa) to affordbiaryl compounds of type (IIIa), which on treatment with allyl bromides(IV) in the presence of a base such as Cs₂CO₃ furnish allyl compounds oftype (Va). Both the compound of formula (IIIa) and the compound offormula (IVa) are functionalized with appropriate L and L¹ groupsrespectively to produce the desired X¹ group after reaction. Variationof the identity of the groups L and L¹ easily allows for entry into thewide range of different X¹ groups contemplated by the present invention.Substitution with an appropriately functionalized aniline (VIa) understandard conditions affords terminal alkenes (VIIa), a key intermediateready for ring closing metathesis (RCM). Once again selection of theappropriately substituted aniline (VIa) allows entry into a wide rangeof possible X² groups contemplated by the present invention. EmployingGrubbs 2^(nd) generation catalyst RCM furnishes (VIIIa) as a mixture oftrans- and cis-isomers which can be separated by chromatography.Compounds of type (IXa) may be obtained by cyclopropanation understandard conditions.

By varying the identities of the starting materials a number ofdifferent combinations of X¹ and X² can be envisaged and produced as cana number of differentially substituted forms of Ar¹ and Ar². In thescheme shown both Ar¹ and Ar² are represented as phenyl moieties,however other aryls can be accessed by employing analogous chemistry asdepicted in Scheme 1. Synthetic procedures for the synthesis of a numberof analogs of the compounds of formula VIIIa are detailed below.

Synthesis of XVIIIb and XVIIIc

Scheme 2 illustrates the procedure used for preparing compounds offormula (XVIIIb and XVIIIc) that can be prepared by analogousprocedures, for example, by the choice of appropriate startingmaterials.

Once again coupling of commercially available 2,4-dichloropyrimidine(Ia) under Suzuki coupling conditions with boronic acids of type (XIIa)affords biaryl compounds of type (XIIIa), which on treatment withalkenyl bromides (XIV) in the presence of a base such as Cs₂CO₃ furnishunsaturated ethers of type (XVa). Substitution with aniline (XVIb orXVIc) under standard conditions affords terminal alkenes (XVIIb orXVIIc), a key intermediate ready for ring closing metathesis (RCM).Employing Grubbs 2^(nd) generation catalyst RCM furnishes (XVIIIb orXVIIIc). Compounds of type (XIXb) are obtained by cyclopropanation understandard conditions.

Synthesis of Intermediate XVIb

Aniline (XVIb) is obtained from nitro-aldehyde (XX) by alkylation of thecorresponding alcohol (prepared by reduction of aldehyde (XX) withsodium borohydride) with allyl bromide (IVa1) followed by SnCl₂reduction of the nitro function.

Synthesis of Intermediate XVIc

Aniline (XVIc) is obtained from a 3-nitrophenol by alkylation with allylbromide (Iva1) followed by SnCl₂ reduction.

Synthesis of XVIIId

Scheme 3 illustrates the procedure used for preparing compounds offormula (XVIIId) that can be prepared by analogous procedures, forexample, by the choice of appropriate starting materials.

Coupling of commercially available 2,4-dichloropyrimidine (Ia) underSuzuki coupling conditions with boronic acids of type (XIId) affordsbiaryl compounds of type (XIIIc), which on treatment with allyl bromides(XIVc) in the presence of a base such as Cs₂CO₃ furnish allyl ethers oftype (XVd). Substitution with aniline (XVIb) under standard conditionsaffords terminal alkenes (XVIIId), a key intermediate ready for ringclosing metathesis (RCM). Employing Grubbs 2^(nd) generation catalystRCM furnishes (XVIId). Compounds of type (XIXd) are obtained bycyclopropanation under standard conditions.

Synthesis of XVIIIe-i

Macrocycles containing a five membered heterocyclic ring linked to thepyrimidine system can be prepared by a procedure analogous to thatdescribed for XVIIId by starting from alternative boronic acids.Structures XVIIIe-i below are representative of compounds of this class.

Scheme 4 illustrates the preparation of compounds of type XVIIIe,XVIIIf, XVIIIg and XVIIIh. Coupling of commercially available2,4-dichloropyrimidine (Ia) under Suzuki coupling conditions withboronic acids of type (XIIe-i) affords biaryl compounds of type(XIIIe-i), which on treatment with allyl bromides (XIVc) in the presenceof a base such as Cs₂CO₃ furnish allyl ethers of type (XVe-h). Reactionaniline (XVIb) under standard conditions followed by ring closingmetathesis (RCM) employing Grubbs 2^(nd) generation catalyst thenfurnishes the desired products (XVIIIe-i).

Representative Procedure for the Synthesis of Compounds Type (XVIIIb)3-(2-Chloro-pyrimidin-4-yl)-phenol (XIIIa1)

To a degassed solution of (Ia) (1.0 g, 6.71 mmol) and (XIIa1) (1.1 g,8.05 mmol) in 1,2 dimethoxy ethane (10 mL) was added sequentially,aqueous Na₂CO₃ ((1.06 g, 10.06 mmol) and Pd(PPh₃)₄ (0.387 g, 0.335mmol). The resultant mixture was stirred at 80-85° C. for 4 h, cooled to0° C. and quenched with saturated NH₄Cl. The product was extracted withCH₂Cl₂ thrice and the combined organic extracts were washed brine, driedover Na₂SO₄ and concentrated under reduced pressure. The crude mixturewas column purified (EtOAc/Hexane) to furnish 0.450 g of (XIIIa1). LC-MS(ESI positive mode) m/z 207 ([M+H]⁺); ¹H NMR (400 MHz, CDCl₃): δ 9.74(s, 1H), 9.23 (d, 1H), 8.83 (d, 1H), 8.01 (dd, 1H), 7.60-7.65 (m, 1H),7.35 (t, 1H), 6.94-6.99 (m, 1H).

4-(3-But-3-enyloxy-phenyl)-2-chloro-pyrimidine (XVa1)

To a mixture of (XIIIa1) (2.0 g, 9.68 mmol) and (XIV) (7.8 g, 5.80 mmol)in dry DMF (10 mL) at ambient temperature was added cesium carbonate(14.19 g, 43.55 mmol) and the resulting mixture was stirred at 40° C.for 6 h. The reaction mixture was cooled to 0° C. and quenched with H₂O.The product was extracted with CH₂Cl₂ thrice and the combined organicextracts were washed with H₂O followed by brine, dried over Na₂SO₄ andconcentrated under reduced pressure to furnish an oil, which waspurified by column (EtOAc/Hexane) to obtain 1.61 g of (XVa1). LC-MS (ESIpositive mode) m/z 261 ([M+H]⁺); ¹H NMR (400 MHz, DMSO d₆): δ 8.82 (d,1H), 8.12 (d, 1H), 7.77 (d, 1H), 7.70 (br s, 1H), 7.48 (t, 1H), 7.18(dd, 1H), 5.86-5.98 (m, 1H), 5.16-5.24 (m, 1H), 5.09-5.13 (m, 1H), 4.13(t, 2H), 2.49-2.56 (m, 2H).

(3-Nitro-phenyl)-methanol (XXIb)

To a solution of (XXb) (5 g, 33.1 mmol) in MeOH (25 mL) at ambienttemperature was added NaBH₄ (1.25 g, 33.1 mmol) and the resultingmixture was stirred for 30 min. The reaction mixture was quenched withwater. The product was extracted with CH₂Cl₂ thrice and the combinedorganic extracts were washed with H₂O followed by brine, dried overNa₂SO₄ and concentrated under reduced pressure to furnish withoutpurification 5 g of compound (XXIb). LC-MS (ESI positive mode) m/z 154([M+H]⁺); ¹H NMR (CDCl₃) δ 8.27 (s, 1H), 8.17 (dd, 1H), 7.73 (dd, 1H),7.57 (t, 1H), 4.85 (s, 2H), 2.07 (s, 1H).

1-Allyloxymethyl-3-nitro-benzene (XXIIb)

To a mixture of (XXIb) (5 g, 32.6 mmol) and allyl bromide (11.3 ml,130.4 mmol) at ambient temperature was added KOH (3.65 g, 65.2 mmol) andTBAI (602 mg, 1.63 mmol) and the resulting mixture was stirred at 40° C.overnight. The reaction mixture was cooled and quenched with H₂O. Theproduct was extracted with CH₂Cl₂ thrice and the combined organicextracts were washed with H₂O followed by brine, dried over Na₂SO₄ andconcentrated under reduced pressure to furnish an oil, which waspurified by column (EtOAc/Hexane: 9/1) to obtain 6.3 g of (XXIIb). LC-MS(ESI positive mode) m/z 194 ([M+H]⁺); ¹H NMR (CDCl₃) δ 8.27 (s, 1H),8.18 (dd, 1H), 7.73 (dd, 1H), 7.57 (t, 1H), 6.01 (m, 1H), —5.38 (m, 1H),5.29 (m, 1H), 4.65 (s, 2H), 4.13 (dt, 2H).

3-Allyloxymethyl-phenylamine (XVIb1)

To a solution of (XXIIb) (10 g, 51.75 mmol) in MeOH/CH₂Cl₂ (1:1, 150 mL)at ambient temperature was added SnCl₂.2H₂O (46.7 g, 207 mmol) and theresulting mixture was stirred overnight. The reaction mixture was cooledto 0° C. and quenched with saturated Na₂CO₃. The product was extractedwith CH₂Cl₂ thrice and the combined organic extracts were washed withH₂O followed by brine, dried over Na₂SO₄ and concentrated under reducedpressure to furnish an oil, which was purified by column (EtOAc/Hexane:5/1) to obtain 6.80 g of (XVIb1) in 80% yield. LC-MS (ESI positive mode)m/z 164 ([M+H]⁺); ¹H NMR (CDCl₃) δ 7.17 (t, 1H), 6.79 (m, 2H), 6.68 (d,1H), 5.95-6.06 (m, 1H), 5.33 (m, 1H), 5.29 (m, 1H), 4.49 (s, 2H), 4.06(m, 2H), 3.38 (s, 2H).

(3-Allyloxymethyl-phenyl)-[4-(3-but-3-enyloxy-phenyl)-pyrimidin-2-yl]-amine(XVIIb1)

To a mixture of (XVa1) (100 mg, 0.38 mmol) and (XVIb1) (93.9 mg, 0.57mmol) in n-butanol (15 mL) at ambient temperature was added 1N HCl (1.0mL) and the resulting mixture was stirred at 100° C. for overnight. Thereaction mixture was cooled to 0° C. and quenched with H₂O. The productwas extracted with CH₂Cl₂ thrice and the combined organic extracts werewashed with saturated NaHCO₃ followed by brine, dried over Na₂SO₄ andconcentrated under reduced pressure to furnish an oil, which waspurified by column (EtOAc/Hexane) to obtain 70 mg of (XVIIb1) in 47%. ¹HNMR (CDCl₃) δ 8.38 (d, 1H), 7.59-7.62 (m, 3H), 7.58 (d, 1H), 7.41 (s,1H), 7.32 (t, 1H), 7.26 (t, 1H), 7.08 (d, 1H), 6.96-6.98 (m, 2H),5.80-5.94 (m, 2H), 5.25 (m, 1H), 5.10-5.15 (m, 2H), 5.06 (m, 1H), 4.48(s, 2H), 4.04 (t, 2H), 3.99 (m, 2H), 2.50 (m, 2H).

Macrocycle Example 1 Compound 1

To a degassed solution of (XVIIb1) (20 mg, 0.05 mmol) and TFA (14 mg,0.125 mmol) in CH₂Cl₂ (200 mL) at ambient temperature was added Grubbs2^(nd) generation catalyst (7 mg, 0.005 mmol). The resulting mixture wasstirred at 50° C. for overnight. The reaction mixture was cooled andconcentrated under reduced pressure to furnish an oil, which waspurified by preparative HPLC to obtain 9 mg of (1). HPLC purity at 254nm: 95%; LC-MS (ESI positive mode) m/z 360 ([M+H]⁺); ¹H NMR (CDCl₃) δ11.75 (s, 1H), 8.38 (m, 1H), 8.18 (d, 1H), 7.92 (m, 1H), 7.41-7.42 (m,1H), 7.30 (t, 1H), 7.23 (d, 1H, CH), 7.10-7.20 (m, 3H), 5.61-5.73 (m,2H, J_(trans)=16.0 Hz), 4.51 (s, 2H), 4.11 (t, 2H), 4.08 (d, 2H), 2.48(q, 2H).

Representative Procedure for the Synthesis of Compounds Type (XVIIIc)1-Allyloxy-3-nitro-benzene (XXIIc)

Compound (XXIIc) was obtained using the same procedure described forcompound (XXIIb); LC-MS (ESI positive mode) m/z 180 ([M+H]⁺).

3-Allyloxy-phenylamine (XVIc1)

Compound (XVIc1) was obtained using the same procedure described forcompound (XVIb1) LC-MS (ESI positive mode) m/z 150 ([M+H]⁺).

(3-Allyloxy-phenyl)-[4-(3-but-3-enyloxy-phenyl)-pyrimidin-2-yl]-amine(XVIIc1)

Compound (XVIIc1) was obtained using the same procedure described forcompound (XVIIb1); LC-MS (ESI positive mode) m/z 374 ([M+H]⁺).

Macrocycle Example 2 Compound 12

Compound (12) was obtained using the same procedure described forcompound (1) HPLC purity at 254 nm: 99%; LC-MS (ESI positive mode) m/z346 ([M+H]⁺); ¹H NMR (CDCl₃) δ 11.30 (s, 1H), 8.29 (d, 1H), 8.21 (t,1H), 8.11 (t, 1H), 7.57 (d, 1H), 7.48 (t, 1H), 7.32-7.35 (m, 2H),7.22-7.25 (m, 1H), 6.95 (dd, 1H), 6.82 (dd, 1H), 6.02-6.08 (m, 1H, CH═,J_(trans)=11 Hz), 5.87-5.93 (m, 1H, CH═, J_(trans)=11 Hz), 4.78 (d, 2H),4.29 (t, 2H), 2.63-2.68 (m, 2H).

Representative Procedure for the Synthesis of Compounds Type (XVIIId)[3-(2-Chloro-pyrimidin-4-yl)-phenyl]-methanol (XIIIa2)

Compound (XIIIa2) was obtained using the same procedure described forcompound (XIIIa1); LC-MS (ESI positive mode) m/z 221 ([M+H]⁺).

4-(3-Allyloxymethyl-phenyl)-2-chloro-pyrimidine (XVa2)

Compound (XVa2) was obtained using the same procedure described forcompound (XVa1); LC-MS (ESI positive mode) m/z 271 ([M+H]⁺).

2-(2-Chloro-ethoxy)-5-nitro-benzaldehyde (XXId)

To a mixture of (XXd) (1.0 g, 5.98 mmol) and bromochloroethane (996 L,11.96 mmol) in dry DMF (15 mL) at ambient temperature was addedpotassium carbonate (1.64 gg, 11.96 mmol) and the resulting mixture wasstirred at 60° C. overnight. The reaction mixture was cooled to 0° C.and quenched with H₂O. The product was extracted with CH₂Cl₂ thrice andthe combined organic extracts were washed with H₂O followed by brine,dried over Na₂SO₄ and concentrated under reduced pressure to furnish1.29 g of a yellow solid (XXId) in 94% yield. LC-MS (ESI positive mode)m/z 229 ([M+H]⁺); ¹H NMR (CDCl₃) δ 10.56 (s, 1H), 8.78 (d, 1H), 8.50(dd, 1H), 7.15 (d, 1H), 4.54 (t, 2H), 3.99 (t, 2H).

[2-(2-Chloro-ethoxy)-5-nitro-phenyl]-methanol (XXIId)

Compound (XXIId) was obtained using the same procedure described forcompound (XXIb). LC-MS (ESI positive mode) m/z 232 ([M+H]⁺).

2-Allyloxymethyl-1-(2-chloro-ethoxy)-4-nitro-benzene (XXIIId)

Compound (XXIIId) was obtained using the same procedure described forcompound (XXIIb); LC-MS (ESI positive mode) m/z 272 ([M+H]⁺).

1-[2-(2-Allyloxymethyl-4-nitro-phenoxy)-ethyl]-pyrrolidine (XXIVd)

To a solution of (XXIIId) (1 g, 3.68 mmol) in DMA (10 mL) was addedpyrrolidine (0.61 mL, 7.36 mmol) and the resulting mixture was stirredovernight at 60° C. The reaction mixture was quenched with water. Theproduct was extracted with CH₂Cl₂ thrice and the combined organicextracts were washed with H₂O followed by brine, dried over Na₂SO₄ andconcentrated under reduced pressure to furnish without purification 750mg of compound (XXIVd) with 70% yield. LC-MS (ESI positive mode) m/z 307([M+H]⁺).

3-Allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (XVIb2)

Compound (XVIb2) was obtained using the same procedure described forcompound (XVIb); LC-MS (ESI positive mode) m/z 277 ([M+H]⁺).

[4-(3-Allyloxymethyl-phenyl)-pyrimidin-2-yl]-[3-allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine(XVIId1)

Compound (XVIId1) was obtained using the same procedure described forcompound (XVIIb1); LC-MS (ESI positive mode) m/z 501.

Macrocycle Example 3 Compound 13

Compound (13) was obtained using the same procedure described forcompound (1) HPLC purity at 254 nm: 99%; LC-MS (ESI positive mode) m/z473 ([M+H]⁺); ¹H NMR (MeOD-d₄) δ 8.79 (d, 1H), 8.46 (d, 1H), 8.34-8.31(m, 1H), 7.98-7.96 (m, 1H), 7.62-7.49 (m, 2H), 7.35 (d, 1H), 7.15-7.10(m, 1H), 7.07-7.02 (m, 1H), 5.98-5.75 (m, 2H, 2×=CH), 4.67 (s, 2H), 4.67(s, 2H), 4.39-4.36 (m, 2H), 4.17 (d, 2H), 4.08 (d, 2H), 3.88-3.82 (m,2H), 3.70 (t, 2H), 2.23-2.21 (m, 2H), 2.10-2.07 (m, 2H).

Macrocycle Example 4 Compound 53

To solution of (13) (0.02 g) in CH₂Cl₂ (2 mL) dioxane mixture (1 mL) at0° C. was added 5 mole % of Pd(OAc)₂. Then freshly prepared etherealsolution of CH₂N₂ was added slowly. The resulting mixture was stirred at0° C. for 3 h. The reaction mixture was then concentrated under reducedpressure to furnish oil, which was purified by preparative HPLC toobtain 0.005 g of (53). (CDCl₃) δ 8.78 (br s, 1H), 8.63 (br s, 1H), 8.42(d, 1H), 7.79 (d, 1H), 7.50 (d, 1H), 7.42 (t, 1H), 7.18 (d, 1H), 6.83(m, 2H), 5.12 (d, 1H), 4.87 (d, 1H), 4.72 (d, 1H), 4.61 (d, 1H),4.14-4.19 (m, 2H), 4.03-4.07 (m, 2H), 2.99 (t, 2H), 2.81-2.86 (m, 1H),2.74 (br s, 4H), 2.66-2.71 (m, 1H), 1.81-1.86 (m, 4H), 1.04-1.15 (m,2H), 0.28-0.33 (m, 1H), 0.15-0.20 (m, 1H).

Representative Procedure for the Synthesis of Compounds Type (XVIIIe)5-(2-Chloro-pyrimidin-4-yl)-thiophene-2-carbaldehyde (XIIIe1)

To a solution of 1,4 dioxane, 2,4 dichloropyrimidine was added and thereaction evacuated & purged with N₂. Then dppf catalyst([1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) was addedand the system was evacuated and purged with N₂ again. Then (XIIe1) andsaturated bicarbonate solution was added sequentially and the solutionstirred at 85° C. under N₂ for 1 hr. The solution was cooled andfiltered through celite and washed with DCM thrice. The DCM layer wasextracted with water. The water layer was extracted with DCM and all DCMlayers were dried over Na₂SO₄ and removed in vacuo. The crude waspurified by flash chromatography eluting with 40% ethyl acetate inhexane to yield a pale yellow solid (XIIIe1) (50%). LC-MS (ESI positivemode) m/z 225 ([M+H]⁺); ¹H NMR (CDCl₃) δ 10.64 (s, 1H), 8.68 (d, 1H),7.66 (m, 2H), 7.57 (d, 1H).

[5-(2-Chloro-pyrimidin-4-yl)-thiophen-2-yl]-methanol (XIIIe2)

Compound (XIIIe2) was obtained using the same procedure described forcompound (XXIb) with a yield of 90%. LC-MS (ESI positive mode) m/z 227([M+H]⁺); ¹H NMR (CDCl₃) δ 8.62 (d, 1H), 7.55 (m, 2H), 7.25 (d, 1H),4.83 (s, 2H), 4.68 (bs, 1H).

4-(5-Allyloxymethyl-thiophen-2-yl)-2-chloro-pyrimidine (XVe1)

Compound (XVe1) was obtained using the same procedure described forcompound (XXIIb) with a yield of 80%. LC-MS (ESI positive mode) m/z 267([M+H]⁺)

[3-Allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(5-allyloxymethyl-thiophen-2-yl)-pyrimidin-2-yl]-amine(XVIIe1)

Compound (XVIIe1) was obtained using the same procedure described forcompound (XVIIb1); LC-MS (ESI positive mode) m/z 507.

Macrocycle Example 5 Compound 48

Compound (48) was obtained using the same procedure described forcompound (1) HPLC purity at 254 nm: 100%; LC-MS (ESI positive mode) m/z479 ([M+H]⁺); ¹H NMR (MeOD-d4): δ 8.66 (d, 1H), 8.32 (d, 1H), 7.81 (d,1H), 7.27 (d, 1H), 7.12 (dd, 1H), 7.07-7.02 (m, 2H), 6.08 (dt, 1H, CH,J=4.4 Hz, J_(trans)=15.6 Hz), 5.98 (dt, 1H, CH, J=4.6 Hz, J_(trans)=15.6Hz), 4.61 (s, 2H), 4.38 (t, 2H), 4.18 (d, 4H), 3.81 (br s, 2H), 3.69 (t,2H), 3.37-3.35 (m, 2H), 2.22-2.08 (m, 6H).

Representative Procedure for the Synthesis of Compounds Type (XVIIIf)5-(2-Chloro-pyrimidin-4-yl)-furan-2-carbaldehyde (XIIIf1)

Compound (XIIIf1) was obtained using the same procedure described forcompound (XIIIe1); LC-MS (ESI positive mode) m/z 209 ([M+H]⁺)

[5-(2-Chloro-pyrimidin-4-yl)-furan-2-yl]-methanol (XIIIf2)

Compound (XIIIf2) was obtained using the same procedure described forcompound (XXIb); LC-MS (ESI positive mode) m/z 211 ([M+H]⁺).

4-(5-Allyloxymethyl-furan-2-yl)-2-chloro-pyrimidine (XVf1)

Compound (XVf1) was obtained using the same procedure described forcompound (XXIIb); LC-MS (ESI positive mode) m/z 251 ([M+H]⁺).

[4-(5-Allyloxymethyl-furan-2-yl)-pyrimidin-2-yl]-[3-allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine(XVIIf1)

Compound (XVIIf1) was obtained using the same procedure described forcompound (XVIIb1); LC-MS (ESI positive mode) m/z 491.

Macrocycle Example 6 Compound 38

Compound (38) was obtained using the same procedure described forcompound (1) HPLC purity at 254 nm: 99%; LC-MS (ESI positive mode) m/z463 ([M+H]⁺); ¹H NMR (MeOD-d₄) δ 8.90 (d, 1H), 8.33 (d, 1H), 7.37 (d,1H), 7.17 (d, 1H), 7.14-7.11 (m, 1H), 7.04 (d, 1H), 6.67 (d, 1H), 6.04(dt, 1H, CH, J=5.2 Hz, J_(trans)=15.8 Hz), 5.96 (dt, 1H, CH, J=5.0 Hz,J_(trans)=15.8 Hz), 4.65 (s, 2H), 4.62 (s, 2H), 4.37 (t, 2H), 4.14 (d,2H), 4.09 (d, 2H), 3.81 (br s, 2H), 3.66 (t, 2H), 3.33 (s, 2H),2.21-1.98 (m, 4H).

Representative Procedure for the Synthesis of Compounds Type (XVIIIg1)4-(2-Chloro-pyrimidin-4-yl)-thiophene-2-carbaldehyde (XIIIg1)

Compound (XIIIg1) was obtained using the same procedure described forcompound (XIIIe1); LC-MS (ESI positive mode) m/z 225 ([M+H]⁺).

[4-(2-Chloro-pyrimidin-4-yl)-thiophen-2-yl]-methanol (XIIIg2)

Compound (XIIIg2) was obtained using the same procedure described forcompound (XXIb); LC-MS (ESI positive mode) m/z 227 ([M+H]⁺).

4-(5-Allyloxymethyl-thiophen-3-yl)-2-chloro-pyrimidine (XVg1)

Compound (XVIg1) was obtained using the same procedure described forcompound (XXIIb); LC-MS (ESI positive mode) m/z 267 ([M+H]⁺)

[3-Allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(5-allyloxymethyl-thiophen-3-yl)-pyrimidin-2-yl]-amine(XVIIg1)

Compound (XVIIg1) was obtained using the same procedure described forcompound (XVIIb1); LC-MS (ESI positive mode) m/z 507.

Macrocycle Example 7 Compound 52

Compound (52) was obtained using the same procedure described forcompound (1) HPLC purity at 254 nm: 99%; LC-MS (ESI positive mode) m/z479 ([M+H]⁺); ¹H NMR (MeOD-d₄): δ 9.03 (d, 1H), 8.86 (d, 1H), 8.81 (d,1H), 8.26 (s, 1H), 7.81 (d, 1H), 7.59 (dd, 1H), 7.56-7.51 (m, 1H), 6.38(dt, 1H, CH, J=5.7 Hz, J_(trans)=15.7 Hz), 6.31 (dt, 1H, CH, J=5.4 Hz,J_(trans)=15.7 Hz), 5.24 (s, 2H), 5.14 (s, 2H), 4.86 (t, 2H), 4.65 (d,2H), 4.54 (d, 2H), 4.29 (br s, 2H), 4.18 (t, 2H), 3.84-3.83 (m, 2H),2.80-2.48 (m, 4H).

Representative Procedure for the Synthesis of Compounds Type (XVIIIh1)4-(2-Chloro-pyrimidin-4-yl)-furan-2-carbaldehyde (XIIIh1)

Compound (XIIIh1) was obtained using the same procedure described forcompound (XIIIe1); LC-MS (ESI positive mode) m/z 209 ([M+H]⁺)

[4-(2-Chloro-pyrimidin-4-yl)-furan-2-yl]-methanol (XIIIh2)

Compound (XIIIh2) was obtained using the same procedure described forcompound (XXIb); LC-MS (ESI positive mode) m/z 211 ([M+H]⁺).

4-(5-Allyloxymethyl-furan-3-yl)-2-chloro-pyrimidine (XVh1)

Compound (XVh1) was obtained using the same procedure described forcompound (XXIIb); LC-MS (ESI positive mode) m/z 251 ([M+H]⁺).

[4-(5-Allyloxymethyl-furan-3-yl)-pyrimidin-2-yl]-[3-allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine(XVIIh1)

Compound (XVIIh1) was obtained using the same procedure described forcompound (XVIIb1); LC-MS (ESI positive mode) m/z 491.

Macrocycle Example 8 Compound 50

Compound (50) was obtained using the same procedure described forcompound (1) HPLC purity at 254 nm: 99%; LC-MS (ESI positive mode) m/z463 ([M+H]⁺); ¹H NMR (MeOD-d₄): δ 8.56 (d, 1H), 8.38 (d, 1H), 8.29 (brs, 1H), 7.17 (d, 1H), 7.11-7.06 (m, 2H), 7.03-7.01 (m, 1H), 5.99 (dt,1H, CH, J=6.0 Hz, J_(trans)=15.6 Hz), 5.84 (dt, 1H, CH, J=5.8 Hz,J_(trans)=15.6 Hz), 4.66 (s, 2H₂), 4.57 (s, 2H), 4.37 (t, 2H), 4.18 (d,2H), 4.09 (d, 2H), 3.79 (br s, 2H), 3.69 (t, 2H), 3.35-3.34 (m, 2H),2.21-2.07 (m, 4H).

The compounds outlined in Table 1 were synthesized following theprocedures outlined above.

TABLE 1 m/z No Structure ¹H NMR (400 MHz) [MH]⁺ 1

(CDCl₃) δ 11.75 (s, 1H), 8.38 (m, 1H), 8.18 (d, 1H), 7.92 (m, 1H),7.41-7.42 (m, 1H), 7.30 (t, 1H), 7.23 (d, 1H), 7.10-7.20 (m, 3H),5.61-5.73 (m, 2H, J_(trans) = 16.0 Hz), 4.51 (s, 2H), 4.11 (t, 2H), 4.08(d, 2H), 2.48 (q, 2H). 360 2

(CDCl₃) δ 11.81 (s, 1H), 8.15 (m, 1H), 8.14 (d, 1H), 7.60 (m, 1H),7.36-7.37 (m, 2H), 7.31 (t, 1H), 7.23 (m, 1H), 7.17 (d, 1H), 7.14-7.16(m, 1H), 7.10 (d, 1H, CH), 6.02 (dt, 1H, CH═, J_(trans) = 16.0 Hz, J =5.0 Hz), 5.78 (dt, 1H, CH═, J_(trans) = 16.0 Hz, J = 5.0 Hz), 4.61 (d,2H), 4.47 (s, 2H), 4.05 (d, 2H). 346 3

(CDCl₃) δ 11.82 (s, 1H), 8.13 (d, 1H), 8.08 (s, 1H), 7.94-7.99 (m, 1H),7.50 (d, 1H), 7.36 (t, 1H), 7.30-7.35 (m, 2H), 7.22-7.24 (m, 1H), 7.16(d, 1H), 7.12 (d, 1H), 5.78-5.84 (m, 1H, CH═, J_(cis) = 11.0 Hz),5.66-5.72 (m, 1H, CH═, J_(cis) = 11.0 Hz), 4.89 (d, 2H), 4.45 (s, 2H),4.15 (d, 2H). 346 4

(CDCl₃) δ 8.54-8.56 (m, 1H), 8.38 (d, 1H), 8.32 (d, 1H), 7.87 (dd, 1H),7.14-7.17 (m, 2H), 7.31 (t, 1H), 6.98 (d, 1H), 6.91-6.93 (m, 1H),5.89-5.93 (m, 2H), 4.62 (s, 2H), 4.61 (s, 2H), 4.16 (d, 2H), 4.11 (d,2H), 3.95 (s, 3H). 390 5

Mixture of cis and trans 390 6

(CDCl₃) δ 11.76 (s, 1H), 8.16 (d, 1H), 8.14 (d, 1H), 7.66 (s, 1H), 7.40-7.42 (m, 2H), 7.28 (dd, 1H), 7.19- 7.21 (m, 1H), 7.17 (d, 1H), 6.90 (d,1H, 6.07-6.14 (m, 1H, ═CH, J_(trans) = 15.7 Hz), 5.82-5.88 (m, 1H, ═CH,J_(trans) = 15.7 Hz), 5.67 (d, 2H), 4.60 (s, 2H), 4.14 (dd, 2H), 3.86(s, 3H). 376 7

(CDCl₃) δ 11.75 (s, 1H), 8.19 (d, 1H), 7.13 (d, 1H), 8.09 (m, 1H), 7.46(d, 1H), 7.34 (t, 1H), 7.31-7.32 (m, 2H), 7.25-7.26 (m, 1H), 6.94 (d,1H, CH, J = 8.7 Hz), 5.79-5.93 (m, 2H), 5.03 (dd, 2H), 4.62 (s, 2H),4.28 (dd, 2H), 3.90 (s, 3H). 376 8

Mixture of cis and trans 376 9

(DMSO-d₆) δ 9.72 (s, 1H), 8.55 (d, 1H), 8.31 (t, 1H), 7.94 (t, 1H), 7.62(d, 1H), 7.46 (t, 1H), 7.42 (d, 1H), 7.17 (t, 1H), 7.14 (dd, 1H), 6.80(dd, 1H), 6.50 (dd, 1H), 5.53-5.65 (m, 2H, 2XCH═, J_(cis) = 8.8 Hz),4.07 (t, 2H), 3.99 (t, 2H), 2.45-2.50 (m, 4H) 360 10

(DMSO-d₆) δ 9.77 (s, 1H), 8.57 (d, 1H), 8.48 (t, 1H), 8.09 (t, 1H), 7.65(d, 1H), 7.46 (d, 1H), 7.44 (t, 1H), 7.17 (t, 1H), 7.10 (dd, 1H), 6.84(dd, 1H), 6.54 (dd, 1H), 5.60-5.68 (m, 2H, 2XCH═), 4.12 (t, 2H), 4.06(t, 2H), 2.56-2.61 (m, 4H) 360 11

(CDCl₃) δ 11.30 (s, 1H), 8.20-8.29 (m, 2H), 7.94 (t, 1H), 7.85 (t, 1H),7.52-7.56 (m, 1H), 7.48 (t, 1H), 7.33- 7.35 (m, 1H), 7.23-7.26 (m, 1H),6.93 (dd, 1H), 6.85 (dd, 1H), 5.97- 6.00 (m, 2H), 4.71 (m, 2H), 4.27 (t,2H), 2.45-2.50 (m, 2H) 346 12

(CDCl₃) δ 11.30 (s, 1H), 8.29 (d, 1H), 8.21 (t, 1H), 8.11 (t, 1H), 7.57(d, 1H), 7.48 (t, 1H), 7.32-7.35 (m, 2H, 7.22-7.25 (m, 1H), 6.95 (dd,1H), 6.82 (dd, 1H), 6.02-6.08 (m, 1H, CH═, J_(trans) = 11 Hz), 5.87-5.93(m, 1H, CH═, J_(trans) = 11 Hz), 4.78 (d, 2H), 4.29 (t, 2H), 2.63-2.68(m, 2H) 346 13

(MeOD-d₄) δ 8.79 (d, 1H), 8.46 (d, 1H), 8.34-8.31 (m, 1H), 7.98-7.96 (m,1H), 7.62-7.49 (m, 2H), 7.35 (d, 1H), 7.15-7.10 (m, 1H), 7.07-7.02 (m,1H), 5.98-5.75 (m, 2H, 2x═CH), 4.67 (s, 2H), 4.67 (s, 2H), 4.39-4.36 (m,2H), 4.17 (d, 2H), 4.08 (d, 2H), 3.88-3.82 (m, 2H), 3.70 (t, 2H), 2.23-2.21 (m, 2H), 2.10-2.07 (m, 2H) 473 14

(MeOD-d₄) δ 8.50-8.48 (m, 1H), 8.37 (d, 1H), 8.27 (d, 1H), 8.07 (dd,1H), 7.38 (d, 1H), 7.17-7.15 (m, 2H), 7.08-7.06 (m, 1H), 5.98-5.86 (m,2H), 4.69 (s, 2H), 4.64 (s, 2H), 4.39 (t, 2H), 4.17 (d, 2H), 4.08 (d,2H), 3.88-3.82 (m, 2H), 3.70 (t, 2H), 2.23- 2.21 (m, 2H), 2.10-2.07 (m,2H). 503 15

(MeOD-d₄): δ 8.49 (s, 1H), 7.98-7.97 (m, 1H), 7.77 (s, 1H), 7.63-7.61(m, 1H), 7.57-7.55 (m, 1H), 7.42-7.38 (m, 4H), 7.14-7.11 (m, 1H), 5.83-5.76 (m, 1H, ═CH), 5.42-5.34 (m, 1H, ═CH), 4.29-4.27 (m, 1H, CH2),4.13-4.10 (m, 2H), 3.83-3.72 (m, 2H), 3.24 (s, 2H), 3.25-2.97 (m, 4H),2.29-2.24 (m, 2H), 2.11-1.92 (m, 4H) 475 16

Mixture of cis and trans 491 17

Mixture of cis and trans 461 18

(CDCl₃) δ 12.11 (s, 1H), 8.21 (d, 1H), 8.09 (d, 1H), 7.88 (d, 1H), 7.57(dd, 1H), 7.31-7.28 (m, 1H), 7.24- 7.17 (m, 1H), 6.99 (d, 1H), 6.88(d,), 5.94 (dt, 1H, CH, J = 7.6 Hz, J = 10.8 Hz), 5.82 (dt, J = 6.7 Hz,J = 10.8 Hz 1H), 4.51 (s, 2H), 4.42 (br s, 2H), 4.23-4.09 (m, 4H), 3.98(s, 3H), 3.61 (br s, 2H), 3.36 (t, 4H), 2.70- 2.60 (m, 2H), 1.41 (t,6H). 505 19

(CDCl₃) δ 12.01 (s, 1H), 8.58 (d, 1H), 8.28-8.15 (m, 1H), 7.96-7.84 (m,1H), 7.52-7.44 (m, 2H), 7.31- 7.27 (m, 1H), 7.25-7.24 (m, 1H), 7.21-7.18(m, 1H), 6.88-6.85 (m, 1H), 5.81 (dt, 1H, J = 6.0 Hz, J_(trans) = 15.4Hz), 5.69 (dt, 1H, J = 6.6 Hz, J_(trans) = 15.4 Hz), 4.99 (s, 2H), 4.39(brs, 2H), 4.31-4.25 (m, 2H), 4.07- 4.00 (m, 2H), 3.60 (br s, 2H), 3.37-3.34 (m, 4H), 2.61-2.44 (m, 2H), 1.41 (t, 6H). 475 20

(CDCl₃) δ 12.01 (s, 1H), 8.29 (d, 1H), 8.08 (d, 1H), 7.96 (d, 1H), 7.66(dd, 1H), 7.31-7.27 (m, 1H), 7.23- 7.21 (m, 1H), 7.02 (d, 1H), 6.87 (d,1H), 5.93 (dt, 1H, CH, J = 6.3 Hz, J_(trans) = 15.6 Hz), 5.73 (dt, 1H,CH, J = 5.6 Hz, J_(trans) = 15.6 Hz), 4.55 (s, 2H), 4.37 (br s, 2H),4.30-4.25 (m, 2H), 4.08 (d, 2H), 3.97 (s, 3H), 3.6 (br s, 2H), 3.37-3.26(m, 4H), 2.46- 2.42 (m, 2H), 1.41 (t, 6H). 505 21

(DMSO-d₆) δ 9.53 (s, 1H), 9.41 (s, 1H), 8.49 (d, 1H), 8.47 (d, 1H), 8.17(d, 1H), 8.07 (dd, 1H), 7.36 (d, 1H), 7.17 (dd, 1H, 7.03 (d, 1H),5.77-5.83 (m, 1H, ═CH, J_(trans) = 14.4 Hz), 5.51- 5.59 (m, 1H, ═CH,J_(trans) = 14.4 Hz), 4.52 (d, 4H), 4.30 (t, 2H), 4.08 (d, 4H), 4.03 (d,2H), 3.89 (s, 3H), 3.57 (q, 2H), 3.24-3.35 (m, 4H), 2.08 (s, 2H), 1.28(t, 6H). 506 22

(CDCl₃) δ 11.92 (s, 1H), 8.15 (d, 1H), 8.10 (br s, 1H), 7.26 (d, 1H),7.52 (dd, 1H), 7.31-7.29 (m, 1H), 7.18 (d, 1H), 6.99 (d, 1H), 6.89 (d,1H), 6.08 (dt, 1H, CH, J = 5.6 Hz, J_(trans) = 15.7 Hz), 5.83-5.74 (m,1H, CH), 4.7 (d, 2H), 4.58 (s, 2H), 4.41 (s, 2H), 4.09 (d, 2H), 3.98 (s,3H), 3.60 (s, 2H), 3.23-2.85 (m, 3H), 2.13 (br s, 5H). 489 23

(CDCl₃) δ 8.20 (br s, 1H), 8.04 (dd, 2H), 7.64 (dd, 1H), 7.27-7.25 (m,1H), 7.02-6.99 (m, 1H), 6.96-6.92 (m, 1H), 7.31-7.29 (m, 1H), 5.99 (dt,1H, CH, J = 5.3 Hz, J_(ciss) = 11.1 Hz), 5.79 (dt, 1H, CH, J = 4.7 Hz,J_(ciss) = 11.2 Hz), 5.83-5.74 (m, 1H, CH), 4.92 (d, 2H), 4.54 (s, 2H),4.44-4.42 (m, 2H), 4.19 (d, 2H), 3.99 (s, 3H), 3.62-3.60 (m, 2H),3.43-3.37 (m, 1H), 2.13 (br s, 5H). 489 24

(CDCl₃) δ 11.95 (s, 1H), 8.22 (d, 1H), 8.14 (d, 1H), 7.91 (d, 1H, 7.60(dd, 1H), 7.35-7.32 (m, 1H), 7.27 (d, 1H), 7.03 (d, 1H), 6.90 (d, 1H),5.94 (dt, 1H, J = 7.7 Hz, J_(cis) = 10.8 Hz), 5.86 (dt, 1H, CH, J = 6.9Hz, J_(cis) = 10.8 Hz), 4.55 (s, 2H), 4.45 (br s, 2H), 4.26-4.13 (m,4H), 4.01 (s, 3H), 3.65 (br s, 2H), 3.09-2.91 (m, 3H), 2.72-2.62 (m,2H), 2.21-2.06 (br s, 5H). 503 25

(CDCl₃) δ 8.31 (d, 1H), 8.18 (d, 1H), 7.97 (d, 1H), 7.69 (dd, 1H), 7.26(d, 1H), 7.03 (d, 1H), 6.91 (d, 1H), 5.95 (dt, 1H, CH, J = 6.3 Hz,J_(trans) = 15.6 Hz), 5.73 (dt, 1H, CH, J = 5.3 Hz, J_(trans) = 15.6Hz), 4.58 (s, 2H), 4.42-4.37 (m, 2H), 4.29 (t, 2H), 3.65 (br s, 2H),4.09 (d, 2H), 3.97 (s, 3H), 3.62-3.57 (m, 2H), 2.45-2.38 (m, 3H), 2.14(br s, 5H). 503 26

(CDCl₃) δ 8.24-8.14 (m, 1H), 8.00- 7.94 (m, 1H), 7.61-7.92 (m, 1H),7.41-7.37 (m, 1H), 7.33-7.31 (m, 1H), 7.24-7.15 (m, 2H), 6.88 (dd, 1H),6.06 (dt, 1H, CH, J = 5.3 Hz, J_(trans) = 15.8 Hz), 5.90-5.71 (m, 1H),4.84 (d, 1H), .4.65 (d, 1H), 4.54 (s, 1H), 4.49 (s, 1H), 4.40-4.33, (m,2H), 4.15 (d, 1H), 4.06 (dd, 1H), 3.88 (br s, 2H), 3.57 (br s, 2H),3.41-3.37 (m, 2H), 2.13 (br s, 4H). 459 27

(CDCl₃) δ 8.67 (d, 1H), 8.30 (d, 1H), 8.01-7.88 (m, 1H), 7.56-7.40 (m,2H), 7.26-7.24 (m, 1H), 7.20-7.16 (m, 2H), 6.95-6.83 (m, 1H), 5.82 (dt,1H, CH, J = 6.0 Hz, J_(trans) = 15.5 Hz), 5.76-5.67 (m, 1H), 4.58-4.53(m, 2H), 4.40-4.39 (m, 2H), 4.30-4.21 (m, 2H), 4.08-4.01 (m, 2H), 3.91(br s, 2H), 3.61-3.60, (m, 2H), 3.39-3.34 (m, 2H), 2.63-2.49 (m, 2H),2.13 (br s, 4H). 473 28

(DMSO-d₆) δ 9.67 (s, 1H), 8.69 (d, 1H), 8.56 (d, 1H), 7.64 (s, 1H), 7.47(d, 1H), 7.39 (d, 1H), 7.17-7.21 (m, 2H), 7.01 (d, 1H), 5.73-5.85 (m,1H, ═CH, J_(trans) = 15.3 Hz), 5.57-5.64 (m, 1H, ═CH, J_(trans) = 15.3Hz), 4.45 (s, 2H), 4.26-4.31 (m, 4H), 4.0 (d, 2H), 3.53-3.57 (m, 2H),3.28-3.31 (m, 4H), 2.43-2.45 (m, 2H), 1.28 (t, 6H). 493 29

(DMSO-d₆) δ 9.83 (s, 1H), 9.64 (s, 1H), 8.75 (d, 1H), 8.44 (s, 1H), 7.52(t, 1H), 7.45 (t, 1H), 7.28-7.33 (m, 2H), 7.18 (dd, 1H), 7.12 (d, 1H),6.13-6.20 (m, 1H, ═CH, J_(trans) = 15.3 Hz), 5.73-5.81 (m, 1H, ═CH,J_(trans) = 15.3 Hz), 4.21-4.31 (m, 4H), 3.80-3.99 (m, 6H), 3.25-3.29(m, 4H), 2.59-2.61 (m, 2H), 2.34 (s, 3H), 1.28 (t, 6H). 489 30

(CDCl₃) δ 11.97 (s, 1H), 8.69 (d, 1H), 8.24 (d, 1H), 7.95 (br s, 1H),7.54-7.45 (m, 2H), 7.35-7.32 (m, 2H), 7.22-7.15 (m, 2H), 5.83 (dt, 1H,CH, J = 6.0 Hz, J_(trans) = 15.4 Hz), 5.69 (dt, 1H, CH, J = 6.7 Hz,J_(trans) = 15.4 Hz), 4.72 (s, 2H), 4.25-4.20 (m, 2H), 4.14 (d, 2H),4.01-3.99 (m, 4H), 3.26-3.22 (m, 4H), 2.56-2.52 (m, 2H). 445 31

(CDCl₃) δ 11.47 (s, 1H), 8.24 (d, 1H), 8.18 (d, 1H), 8.09 (br t, 1H),7.55 (d, 1H), 7.42 (t, 1H) 7.32-7.31 (m, 1H), 7.22-7.19 (m, 1H), 7.12(d, 1H), 5.89 (dt, 1H, CH, J = 5.2 Hz, J_(cis) = 11.4 Hz), 5.73 (dt, 1H,CH, J = 4.4 Hz, J_(cis) = 11.4 Hz), 5.02-5.01 (m, 2H), 4.62 (s, 2H),4.21-4.20 (m, 2H), 3.87-3.85 (m, 4H), 3.00-2.98 (m, 4H). 431 32

(CDCl₃) δ 8.33-8.28 (m, 2H), 8.10 (d, 1H), 7.93 (d, 1H), 7.79 (d, 1H),7.63 (t, 1H), 7.40 (d, 1H), 6.93 (d, 1H), 5.94-5.82 (m, 2H), 4.68 (s,1H), 4.60 (s, 2H), 4.36 (m, 2H), 4.18 (d, 2H), 4.11 (d, 2H), 4.12-4.03(m, 2H), 3.94 (s, 3H), 3.63 (m, 2H), 3.19 (m, 2H), 2.34-2.22 (m, 4H) 50233

(CDCl₃) δ 11.56 (s, 1H), 8.45 (d, 1H), 8.29-8.27 (m, 1H), 8.22 (d, 1H),7.90 (d, 1H), 7.76 (d, 1H), 7.59 (t, 1H), 7.31 (d, 1H), 7.26-7.21 (m,1H), 7.10 (d, 1H), 5.91-5.69 (m, 2H, 2xC═CH), 4.66 (s, 2H), 4.64 (s,2H), 4.17-4.15 (m, 2H), 4.06-4.04 (m, 2H), 3.89-3.82 (m, 4H), 2.30-2.96(m, 4H) 445 348

(CDCl₃) δ 11.69 (s, 1H), 8.31 (d, 1H), 8.28 (d, 1H), 8.09 (d, 1H), 8.31(dd, 1H), 7.25-7.21 (m, 2H), 7.09 (d, 1H), 6.99 (d, 1H), 5.98-5.85 (m,2H, 2xC═CH), 4.67 (s, 2H), 4.61 (s, 2H), 4.19 (d, 2H), 4.10 (d, 2H),3.98 (s, 3H), 3.93-3.86 (m, 4H), 2.95 (t, 2H) 475 35

(MeOD-d₄) δ 8.69 (d, 1H), 8.33 (d, 1H), 7.85 (d, 1H), 7.45 (d, 1H), 7.22(m, 2H), 6.89-6.99 (m, 3H), 5.60- 5.85 (m, 2H), 4.49 (m, 2H), 4.09 (m,4H), 3.92 (m, 2H), 3.60 (m, 2H), 3.40 (m, 2H), 3.15 (m, 2H), 2.39 (m,2H), 2.14 (m, 4H), 1.83 (m, 2H). 487 36

(DMSO-d₆) δ 9.68 (s, 1H), 8.70 (d, 1H), 8.56 (d, 1H), 7.65 (s, 1H), 7.47(d, 1H), 7.50 (d, 1H), 7.17-7.22 (m, 2H), 7.03 (d, 1H), 5.75-5.83 (m,1H, ═CH, J_(trans) = 15.4 Hz), 5.56-5.65 (m, 1H, ═CH, J_(trans) = 15.4Hz), 4.46 (s, 2H), 4.27 (t, 4H), 4.0 (d, 2H), 3.56- 3.69 (m, 6H),23.15-3.21 (m, 2H), 2.03-2.09 (m, 2H), 1.89-1.95 (m, 2H). 491 37

(CDCl₃) δ 8.39 (m, 1H), 8.26 (m, 2H), 7.90 (m, 1H), 7.76 (m, 1H), 7.61(m, 1H), 7.26-7.34 (m, 2H), 6.89 (m, 1H), 5.60-5.95 (m, 2H), 4.65 (m,2H), 4.61 (m, 2H), 4.15 (m, 2H), 4.09 (m, 4H), 3.90 (m, 2H), 3.35 (m,2H), 3.05 (m, 2H), 2.34 (m, 2H), 2.10 (m, 4H). 487 38

(MeOD-d₄) δ 8.90 (d, 1H), 8.33 (d, 1H), 7.37 (d, 1H), 7.17 (d, 1H),7.14- 7.11 (m, 1H), 7.04 (d, 1H), 6.67 (d, 1H), 6.04 (dt, 1H, CH, J =5.2 Hz, J_(trans) = 15.8 Hz), 5.96 (dt, 1H, CH, J = 5.0 Hz, J_(trans) =15.8 Hz), 4.65 (s, 2H), 4.62 (s, 2H), 4.37 (t, 2H), 4.14 (d, 2H), 4.09(d, 2H), 3.81 (br s, 2H) 3.66 (t, 2H), 3.33 (s, 2H), 2.21-1.98 (m, 4H).463 39

(CDCl₃): δ 10.91 (s, 1H), 8.67-8.66 (m, 1H), 8.17-8.14 (m, 1H), 7.37-7.32 (m, 1H), 7.28-7.27 (m, 1H), 7.18-7.16 (m, 2H), 6.97 (d, 1H), 6.65(d, 1H), 6.00 (dt, 1H, CH, J = 5.6 Hz, J_(trans) = 15.8 Hz), 5.89 (dt,1H, CH, J = 5.5 Hz, J_(trans) = 15.8 Hz), 4.61 (s, 2H), 4.58 (s, 2H),4.15 (d, 2H), 4.08 (d, 2H). 350 40

(CDCl₃) δ 10.62 (s, 1H), 8.59 (d, 1H), 8.29-8.24 (m, 2H), 7.88 (d, 1H),7.72 (d, 1H), 7.59-7.56 (m, 1H), 7.30 (d, 1H), 7.18-7.10 (m, 2H),5.90-5.69 (m, 2H), 4.65 (s, 2H), 4.61 (s, 2H), 4.17-4.15 (m, 2H),4.08-4.06 (m, 2H), 3.68-3.66 (m, 2H), 3.37-3.25 (m, 4H), 2.93-2.91 (m,2H), 2.90 (s, 3H) 458 41

(CDCl₃) δ 11.83 (s, 1H), 8.35 (d, 1H), 8.26 (d, 1H), 8.10 (d, 1H), 7.93(dd, 1H) 7.31-7.23 (m, 2H), 7.13 (d, 1H), 7.03 (d, 1H), 5.96-5.86 (m,2H), 4.61 (s, 4H), 4.17-4.15 (m, 2H), 4.11-4.10 (m, 2H), 3.98 (s, 3H),3.68-3.66 (m, 2H), 3.35-3.32 (m, 2H), 3.22-3.08 (m, 2H), 3.08-3.06 (m,2H), 2.90 (s, 3H) 488 42

(CDCl₃) δ 10.92 (s, 1H), 8.25 (d, 1H), 8.21 (d, 1H), 8.18-8.16 (m, 1H),7.80 (dd, 1H), 7.18-7.11 (m, 3H), 6.95 (d, 1H), 5.72-5.64 (m, 2H), 4.54(s, 2H), 4.50 (s, 2H), 4.26-4.25 (m, 2H), 4.18-4.17 (m, 2H), 3.90 (s,3H), 3.61-3.59 (m, 2H), 3.33-3.26 (m, 4H), 3.22-3.08 (m, 2H), 3.05-3.01(m, 2H), 2.85 (s, 3H) 488 43

(MeOD-d₄) δ 8.72 (d, 1H), 8.48 (m, 1H), 8.11 (s, 1H), 7.72 (m, 1H), 7.34(m, 2H), 7.05-7.15 (m, 2H), 5.82- 5.90 (m, 2H), 4.65 (m, 2H), 4.39 (m,2H), 4.16 (m, 2H), 4.09 (m, 2H), 3.80 (m, 2H), 3.71 (m, 2H), 3.27 (m,4H), 2.08-2.24 (m, 4H). 491 44

(MeOD-d₄): δ 8.95 (d, 1H), 8.45 (d, 1H), 7.95 (t, 1H), 7.56 (d, 1H),7.46 (t, 1H), 7.33 (d, 1H), 7.21 (dd, 1H), 7.17-7.15 (m, 1H), 7.12-7.09(m, 1H), 5.89 (dt, 1H, CH, J = 6.1 Hz, J_(trans) = 15.5 Hz), 5.71 (dt,1H, CH, J = 6.7 Hz, J_(trans) = 15.5 Hz), 4.63 (s, 2H), 4.29 (t, 2H),4.13 (d, 2H), 3.60-3.57 (m, 3H), 3.37-3.35 (m, 5H), 2.99 (s, 3H),2.54-2.48 (m, 2H). 458 45

Mixture of cis and trans 488 46

(MeOD-d₄) δ 8.45 (m, 2H), 8.30 (m, 1H), 8.05 (m, 1H), 7.38 (m, 1H), 7.26(m, 1H), 7.16 (m, 1H), 7.08 (m, 1H), 5.90-5.92 (m, 2H), 4.65 (m, 4H),4.39 (m, 2H), 4.16 (m, 2H), 4.09 (m, 2H), 3.85 (m, 2H), 3.71 (m, 2H),3.32 (m, 2H), 2.08-2.25 (m, 4H). 491 47

(MeOD-d₄) δ 8.45 (m, 1H), 8.40 (m, 1H), 8.22 (m, 1H), 8.01 (m, 1H), 7.35(m, 1H), 7.27 (m, 1H), 7.15 (m, 1H), 7.08 (m, 1H), 5.78 (m, 2H), 4.64(m, 2H), 4.61 (m, 2H), 4.40 (m, 2H), 4.31 (m, 2H), 4.21 (m, 2H), 3.81(m, 2H), 3.72 (m, 2H), 3.32 (m, 2H), 2.08- 2.24 (m, 4H). 491 48

(MeOD-d4): δ 8.66 (d, 1H), 8.32 (d, 1H), 7.81 (d, 1H), 7.27 (d, 1H),7.12 (dd, 1H), 7.07-7.02 (m, 2H), 6.08 (dt, 1H, CH, J = 4.4 Hz,J_(trans) = 15.6 Hz), 5.98 (dt, 1H, CH, J = 4.6 Hz, J_(trans) = 15.6Hz), 4.61 (s, 2H), 4.38 (t, 2H), 4.18 (d, 4H), 3.81 (br s, 2H), 3.69 (t,2H), 3.37-3.35 (m, 2H), 2.22-2.08 (m, 6H). 479 49

(CDCl₃): δ 10.4 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 7.78 (s, 1H),7.65-7.36 (m, 3H), 7.07 (d, 1H), 6.78 (d, 1H), 5.84-5.64 (m, 2H), 4.56(s, 2H), 4.42 (s, 2H), 4.31 (br s, 2H), 4.10 (d, 2H), 3.99 (d, 2H), 3.85(m, 2H), 3.50 (m, 2H), 2.97 (m, 2H), 2.26 (s, 3H), 2.05 (m, 4H) 487 50

(MeOD-d₄): δ 8.56 (d, 1H), 8.38 (d, 1H), 8.29 (br s, 1H), 7.17 (d, 1H),7.11-7.06 (m, 2H), 7.03-7.01 (m, 1H), 5.99 (dt, 1H, CH, J = 6.0 Hz,J_(trans) = 15.6 Hz), 5.84 (dt, 1H, CH, J = 5.8 Hz, J_(trans) = 15.6Hz), 4.66 (s, 2H₂), 4.57 (s, 2H), 4.37 (t, 2H), 4.18 (d, 2H), 4.09 (d,2H), 3.79 (br s, 2H), 3.69 (t, 2H), 3.35-3.34 (m, 2H), 2.21-2.07 (m,4H). 463 51

(DMSO-d₆): δ 9.50 (s, 1H), 8.58-8.52 (m, 1H), 8.42-8.41 (m, 1H), 7.73-7.64 (m, 1H), 7.61-7.57 (m, 1H), 7.51-7.44 (m, 2H), 7.15-7.11 (m, 1H),7.08-7.01 (m, 1H), 5.86-5.67 (m, 2H), 4.61-4.55 (m, 2H), 4.45- 4.43 (m,2H), 4.12-4.03 (m, 4H), 3.58-3.54 (m, 2H), 3.22-3.18 (m, 2H), 3.20 (s,3H), 2.46-2.31 (m, 2H), 2.24 (s, 3H) 472 52

(MeOD-d₄): δ 9.03 (d, 1H), 8.86 (d, 1H), 8.81 (d, 1H), 8.26 (s, 1H),7.81 (d, 1H), 7.59 (dd, 1H), 7.56-7.51 (m, 1H), 6.38 (dt, 1H, CH, J =5.7 Hz, J_(trans) = 15.7 Hz), 6.31 (dt, 1H, CH, J = 5.4 Hz, J_(trans) =15.7 Hz), 5.24 (s, 2H), 5.14 (s, 2H), 4.86 (t, 2H), 4.65 (d, 2H), 4.54(d, 2H), 4.29 (br s, 2H), 4.18 (t, 2H), 3.84-3.83 (m, 1H), 2.80- 2.48(m, 5H). 479 53

(CDCl₃) δ 8.78 (br s, 1H), 8.63 (br s, 1H), 8.42 (d, 1H), 7.79 (d, 1H),7.50 (d, 1H), 7.42 (t, 1H), 7.18 (d, 1H), 6.83 (m, 2H), 5.12 (d, 1H),4.87 (d, 1H), 4.72 (d, 1H), 4.61 (d, 1H), 4.14- 4.19 (m, 2H), 4.03-4.07(m, 2H), 2.99 (t, 2H), 2.81-2.86 (m, 1H), 2.74 (br s, 4H), 2.66-2.71 (m,1H), 1.81- 1.86 (m, 4H), 1.04-1.15 (m, 2H), 0.28-0.33 (m, 1H), 0.15-0.20(m, 1H). 487 54

(MeOD-d₄) δ 8.87 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.98 (d, 1H), 7.64(d, 1H), 7.54 (d, 1H), 7.40 (d, 1H), 7.37 (d, 1H), 7.20 (dd, 1H), 6.00-5.78 (m, 2H, J_(trans) = 15.6 Hz), 4.67 (s, 2H), 4.27 (d, 2H), 4.06 (d,2H), 3.40 (t, 2H), 3.15 (t, 2H), 2.89 (s, 6H), 2.76 (s, 3H). 460 55

(MeOD-d₄) δ 8.51 (bs, 1H), 8.34 (bd, 1H), 7.75 (s, 1H), 7.49 (s, 1H),7.11- 7.06 (m, 2H), 7.00 (d, 1H), 6.07 (dt, 1H, J_(trans) = 15.6 Hz, J =5.4 Hz), 5.92 (dt, 1H, J_(trans) = 15.7 Hz, J = 5.0 Hz), 4.63 (s, 2H),4.47 (s, 2H), 4.36 (t, 2H), 4.19 (d, 2H), 4.08 (d, 2H), 3.79 (bs, 2H),3.69 (t, 2H), 3.27-3.25 (m, 2H), 2.21-2.08 (m, 4H). 463 56

(MeOD-d₄) δ 9.26 (bs, 1H, 8.90- 8.87 (m, 2H), 8.61-8.58 (m, 2H), 7.44(d, 1H), 7.15-7.12 (m, 1H), 7.06 (d, 1H), 5.96 (dt, 1H, J_(trans) = 15.7Hz, J = 5.3 Hz), 5.88 (dt, 1H, J_(trans) = 15.7 Hz, J = 5.6 Hz,), 4.77(s, 2H), 4.64 (s, 2H), 4.38 (t, 2H), 4.15 (q, 4H), 3.81 (bs, 2H), 3.70(t, 2H), 3.27- 3.25 (m, 2H), 2.23-1.99 (m, 5H). 474 57

(CDCl3) δ 8.27 (d, 1H), 8.07 (s, 1H), 7.49-7.48 (m, 1H), 7.38 (t, 1H),7.24- 7.21 (m, 2H), 7.11-7.08 (dd, 1H), 6.86 (d, 1H), 4.52 (q, 2H),4.40-4.38 (br, m, 2H), 4.33-4.23 (m, 1H), 4.18- 4.13 (m, 1H), 4.78 (dd,1H), 3.56- 3.53 (m, 2H), 3.33-3.28 (br, m, 4H), 3.03 (dd, 1H), 2.38 (s,3H), 1.38 (t, 6H), 1.22-1.12 (m, 1H), 1.00-0.93 (m, 1H), 0.86-0.77 (m,1H), 0.51- 0.42 (m, 2H). 503 58

(MeOD-d₄) δ 8.61 (d, 1H), 8.36 (d, 1H), 8.07 (s, 1H), 7.59 (d, 1H), 7.53(dd, 1H), 7.19 (d, 1 H), 7.13 (dd, 1H), 7.04 (d, 1H), 5.90 (dt, 1H,J_(trans) = 15.6 Hz, J = 5.6 Hz), 5.79 (dt, 1H, J_(trans) = 15.8 Hz, J =5.9 Hz), 4.61 (s, 2H), 4.59 (s, 2H), 4.37 (t, 2H), 4.11 (d, 2H), 4.08(d, 2H), 3.95 (s, 3H), 3.80 (m, 2H), 3.68 (t, 2H), 2.17 (m, 2H), 2.08(m, 2H), 1.30 (m, 2H). 503 59

(DMSO-d₆) δ 9.29 (s, 1H), 8.78 (s, 1H), 8.63 (d, 1H), 8.57 (s, 1H), 8.52(s, 1H), 7.62 (d, 1H), 7.28 (t, 1H), 7.14 (d, 1H), 6.98 (d, 1H),5.90-5.81 (m, 2H), 4.62 (s, 2H), 4.49 (s, 2H), 4.09-4.05 (m, 4H). 361 60

(MeOD-d₄) δ 9.06 (s, 1H), 8.45 (d, 1H), 7.95 (s, 1H), 7.57-7.32 (m, 4H),7.21-7.18 (m, 2H), 5.97 (dt, J_(trans) = 15.4 Hz, J = 6.1 Hz), 5.77 (dt,J_(trans) = 15.4 Hz, J = 6.1 Hz), 4.63 (s, 2H), 4.50-4.00 (m, 4H), 3.09(t, 2H), 3.08 (s, 3H), 2.91 (s, 3H), 2.88 (s, 3H), 2.55-2.50 (m, 2H),1.32-1.25 (m, 2H). 460

As stated previously in one embodiment of the invention the compoundsare of the formula (III):

Following analogous procedures to the ones described above and by makingappropriate modifications to the starting materials the compounds listedin Table 2 may also be made.

TABLE 2 No R¹ R² X¹ X² Y^(A) R^(10B) R^(11B) III-1 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— H H III-2 H H —OCH₂— —CH₂OCH₂— —CH═CH— H H III-3 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ H III-4 H H —OCH₂CH₂— —CH₂OCH₂——CH═CH— H —OCH₃ III-5 H H —OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₃ III-6 H H—OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ H III-7 H H —OCH₂CH₂— —CH₂CH₂O— —CH═CH— HH III-8 H H —OCH₂CH₂— —CH₂O— —CH═CH— H H III-9 H H —CH₂OCH₂— —CH₂OCH₂——CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-yl III-10 H H —CH₂OCH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂—N(Et)₂ III-11 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂—N(Et)₂ III-12 H H —OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂III-13 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ III-14 H H—OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂ III-15 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ III-16 H H —CH₂OCH₂— —CH₂OCH₂——CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ III-17 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1-yl III-18 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1-yl III-19 H H —OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂-pyrollidin-1-yl III-20 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂-pyrollidin-1-yl III-21 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂—N(Et)₂ III-22 H CH₃ —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂—N(Et)₂ III-23 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-ylIII-24 H H —OCH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-yl III-25 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-yl III-26 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ morpholin-4-yl III-27 H H —OCH₂CH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂CH₂—N(Et)₂ III-28 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂-pyrollidin-1-yl III-29 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂CH₂-pyrollidin- 1-yl III-30 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H4-methy-piperazin-1-yl III-31 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃4-methy-piperazin-1-yl III-32 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂CH₂-pyrollidin- 1-yl III-33 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H4-methy-piperazin-1-yl III-34 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃4-methy-piperazin-1-yl III-35 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂-pyrollidin-1-yl III-36 H CH₃ —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂-pyrollidin-1-yl III-37 H CH₃ —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂CH₂-pyrollidin- 1-yl III-38 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—N(CH₃)CH₂CH₂Et₂ III-39 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1-yl III-40 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃—N(CH₃)CH₂CH₂Et₂ III-41 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—OCH₃III-42 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et III-43 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et III-44 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— H —OCH₂CH₂—OCH₃ ^(A)In each of the compounds listedthe geometry about the double bond may be cis or trans ^(B)The positionof R¹⁰ and R¹¹ may vary depending on the position of the correspondingsubstituent in the relevant starting material

In another embodiment of the invention the compounds are of the formula(IV):

Following analogous procedures to the ones described above and by makingappropriate modifications to the starting materials the compounds listedin Table 3 may also be made.

TABLE 3 No R¹ R² X¹ X² Y^(A) R^(10B) R^(11B) IV-1 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— H H IV-2 H H —OCH₂— —CH₂OCH₂— —CH═CH— H H IV-3 H H—OCH₂— —CH₂OCH₂— —CH═CH— H H IV-4 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃H IV-5 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₃ IV-6 H H —OCH₂— —CH₂OCH₂——CH═CH— H —OCH₃ IV-7 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ H IV-8 H H—OCH₂CH₂— —CH₂CH₂O— —CH═CH— H H IV-9 H H —OCH₂CH₂— —CH₂O— —CH═CH— H HIV-10 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-ylIV-11 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂ IV-12 H H —OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ IV-13 H H —OCH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂—N(Et)₂ IV-14 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂—N(Et)₂ IV-15 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂IV-16 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ IV-17 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ IV-18 H H —OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-yl IV-19 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-yl IV-20 H H —OCH₂——CH₂OCH₂— —CH═CH— H —OCH₂CH₂-pyrollidin-1-yl IV-21 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— H —OCH₂CH₂-pyrollidin-1-yl IV-22 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— F —OCH₂CH₂—N(Et)₂ IV-23 H CH₃ —OCH₂CH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂—N(Et)₂ IV-24 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— Hmorpholin-4-yl IV-25 H H —OCH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-yl IV-26H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-yl IV-27 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ morpholin-4-yl IV-28 H H —OCH₂CH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂CH₂—N(Et)₂ IV-29 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂-pyrollidin-1-yl IV-30 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂CH₂-pyrollidin- 1-yl IV-31 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H4-methy-piperazin-1-yl IV-32 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃4-methy-piperazin-1-yl IV-33 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂CH₂-pyrollidin- 1-yl IV-34 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H4-methy-piperazin-1-yl IV-35 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃4-methy-piperazin-1-yl IV-36 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂-pyrollidin-1-yl IV-37 H CH₃ —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂-pyrollidin-1-yl IV-38 H CH₃ —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂CH₂-pyrollidin- 1-yl IV-39 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—N(CH₃)CH₂CH₂Et₂ IV-40 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1-yl IV-41 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃—N(CH₃)CH₂CH₂Et₂ IV-42 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—OCH₃IV-43 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et IV-44 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et IV-46 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— H —OCH₂CH₂—OCH₃ ^(A)In each of the compounds listedthe geometry about the double bond may be cis or trans ^(B)The positionof R¹⁰ and R¹¹ may vary depending on the position of the correspondingsubstituent in the relevant starting material.

In another embodiment of the invention the compounds are of the formula(V):

Following analogous procedures to the ones described above and by makingappropriate modifications to the starting materials the compounds listedin Table 4 may

TABLE 4 No R¹ R² X¹ X² Y^(A) R^(10B) R^(11B) V-1 H H —OCH₂CH₂— —CH₂OCH₂——CH═CH— H H V-2 H H —OCH₂— —CH₂OCH₂— —CH═CH— H H V-3 H H —OCH₂——CH₂OCH₂— —CH═CH— H H V-4 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ H V-5 HH —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₃ V-6 H H —OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₃ V-7 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ H V-8 H H —OCH₂CH₂——CH₂CH₂O— —CH═CH— H H V-9 H H —OCH₂CH₂— —CH₂O— —CH═CH— H H V-10 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-yl V-11 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂ V-12 H H —OCH₂— —CH₂OCH₂——CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ V-13 H H —OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂—N(Et)₂ V-14 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂V-15 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂ V-16 H H—OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ V-17 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ V-18 H H —OCH₂— —CH₂OCH₂——CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-yl V-19 H H —OCH₂CH₂— —CH₂OCH₂——CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-yl V-20 H H —OCH₂— —CH₂OCH₂— —CH═CH—H —OCH₂CH₂-pyrollidin-1-yl V-21 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂-pyrollidin-1-yl V-22 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂—N(Et)₂ V-23 H CH₃ —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂V-24 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-yl V-25 H H —OCH₂——CH₂OCH₂— —CH═CH— H morpholin-4-yl V-26 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH—H morpholin-4-yl V-27 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃morpholin-4-yl V-28 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂CH₂—N(Et)₂V-29 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— F —OCH₂CH₂-pyrollidin-1-yl V-30 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂CH₂-pyrollidin- 1-yl V-31 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— H 4-methy-piperazin-1-yl V-32 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ 4-methy-piperazin-1-yl V-33 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— F —OCH₂CH₂CH₂-pyrollidin- 1-yl V-34 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— H 4-methy-piperazin-1-yl V-35 H H —OCH₂CH₂— —CH₂OCH₂——CH═CH— —OCH₃ 4-methy-piperazin-1-yl V-36 H H —CH₂OCH₂— —CH₂OCH₂——CH═CH— F —OCH₂CH₂-pyrollidin-1-yl V-37 H CH₃ —CH₂OCH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂-pyrollidin-1-yl V-38 H CH₃ —CH₂OCH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂CH₂-pyrollidin- 1-yl V-39 H H —CH₂OCH₂— —CH₂OCH₂——CH═CH— H —N(CH₃)CH₂CH₂Et₂ V-40 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1-yl V-41 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃—N(CH₃)CH₂CH₂Et₂ V-42 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—OCH₃V-43 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et V-44 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et V-46 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH—H —OCH₂CH₂—OCH₃ ^(A)In each of the compounds listed the geometry aboutthe double bond may be cis or trans ^(B)The position of R¹⁰ and R¹¹ mayvary depending on the position of the corresponding substituent in therelevant starting material.

In another embodiment of the invention the compounds are of the formula(VI):

Following analogous procedures to the ones described above and by makingappropriate modifications to the starting materials the compounds listedin Table 5 may also be made.

TABLE 5 No R¹ R² X¹ X² Y^(A) R^(10B) R^(11B) VI-1 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— H H VI-2 H H —OCH₂— —CH₂OCH₂— —CH═CH— H H VI-3 H H—OCH₂— —CH₂OCH₂— —CH═CH— H H VI-4 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃H VI-5 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₃ VI-6 H H —OCH₂— —CH₂OCH₂——CH═CH— H —OCH₃ VI-7 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ H VI-8 H H—OCH₂CH₂— —CH₂CH₂O— —CH═CH— H H VI-9 H H —OCH₂CH₂— —CH₂O— —CH═CH— H HVI-10 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-ylVI-11 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂ VI-12 H H —OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ VI-13 H H —OCH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂—N(Et)₂ VI-14 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂—N(Et)₂ VI-15 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂VI-16 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ VI-17 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ VI-18 H H —OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-yl VI-19 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂-pyrollidin-1-yl VI-20 H H —OCH₂——CH₂OCH₂— —CH═CH— H —OCH₂CH₂-pyrollidin-1-yl VI-21 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— H —OCH₂CH₂-pyrollidin-1-yl VI-22 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— F —OCH₂CH₂—N(Et)₂ VI-23 H CH₃ —OCH₂CH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂—N(Et)₂ VI-24 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— Hmorpholin-4-yl VI-25 H H —OCH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-yl VI-26H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-yl VI-27 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ morpholin-4-yl VI-28 H H —OCH₂CH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂CH₂—N(Et)₂ VI-29 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂-pyrollidin-1-yl VI-30 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂CH₂-pyrollidin- 1-yl VI-31 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H4-methy-piperazin-1-yl VI-32 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃4-methy-piperazin-1-yl VI-33 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂CH₂-pyrollidin- 1-yl VI-34 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H4-methy-piperazin-1-yl VI-35 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃4-methy-piperazin-1-yl VI-36 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂-pyrollidin-1-yl VI-37 H CH₃ —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂-pyrollidin-1-yl VI-38 H CH₃ —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂CH₂-pyrollidin- 1-yl VI-39 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—N(CH₃)CH₂CH₂Et₂ VI-40 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1-yl VI-41 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃—N(CH₃)CH₂CH₂Et₂ VI-42 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—OCH₃VI-43 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et VI-44 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et VI-46 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— H —OCH₂CH₂—OCH₃ ^(A)In each of the compounds listedthe geometry about the double bond may be cis or trans ^(B)The positionof R¹⁰ and R¹¹ may vary depending on the position of the correspondingsubstituent in the relevant starting material.

In another embodiment of the invention the compounds are of the formula(VII):

Following analogous procedures to the ones described above and by makingappropriate modifications to the starting materials the compounds listedin Table 6 may also be made.

TABLE 6 No R¹ R² X¹ X² Y^(A) R^(10B) R^(11B) VII-1 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— H H VII-2 H H —OCH₂— —CH₂OCH₂— —CH═CH— H H VII-3 H H—OCH₂— —CH₂OCH₂— —CH═CH— H H VII-4 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃H VII-5 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₃ VII-6 H H —OCH₂——CH₂OCH₂— —CH═CH— H —OCH₃ VII-7 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ HVII-8 H H —OCH₂CH₂— —CH₂CH₂O— —CH═CH— H H VII-9 H H —OCH₂CH₂— —CH₂O——CH═CH— H H VII-10 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1- yl VII-11 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂—N(Et)₂ VII-12 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂—N(Et)₂ VII-13 H H —OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂VII-14 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ VII-15 H H—OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—N(Et)₂ VII-16 H H —OCH₂CH₂——CH₂OCH₂— —CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ VII-17 H H —CH₂OCH₂— —CH₂OCH₂——CH═CH— —OCH₃ —OCH₂CH₂—N(Et)₂ VII-18 H H —OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1- yl VII-19 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1- yl VII-20 H H —OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂-pyrollidin-1- yl VII-21 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂-pyrollidin-1- yl VII-22 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂—N(Et)₂ VII-23 H CH₃ —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂—N(Et)₂ VII-24 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-ylVII-25 H H —OCH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-yl VII-26 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— H morpholin-4-yl VII-27 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— —OCH₃ morpholin-4-yl VII-28 H H —OCH₂CH₂— —CH₂OCH₂——CH═CH— H —OCH₂CH₂CH₂—N(Et)₂ VII-29 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂-pyrollidin-1- yl VII-30 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂CH₂— pyrollidin-1-yl VII-31 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H4-methy-piperazin-1-yl VII-32 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃4-methy-piperazin-1-yl VII-33 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂CH₂- pyrollidin-1-yl VII-34 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H4-methy-piperazin-1-yl VII-35 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃4-methy-piperazin-1-yl VII-36 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— F—OCH₂CH₂-pyrollidin-1- yl VII-37 H CH₃ —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂-pyrollidin-1- yl VII-38 H CH₃ —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—OCH₂CH₂CH₂- pyrollidin-1-yl VII-39 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— H—N(CH₃)CH₂CH₂Et₂ VII-40 H H —CH₂OCH₂— —CH₂OCH₂— —CH═CH— —OCH₃—OCH₂CH₂-pyrollidin-1- yl VII-41 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— —OCH₃—N(CH₃)CH₂CH₂Et₂ VII-42 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—OCH₃VII-43 H H —OCH₂CH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et VII-44 H H—CH₂OCH₂— —CH₂OCH₂— —CH═CH— H —OCH₂CH₂—SO₂Et VII-46 H H —CH₂OCH₂——CH₂OCH₂— —CH═CH— H —OCH₂CH₂—OCH₃ ^(A)In each of the compounds listedthe geometry about the double bond may be cis or trans ^(B)The positionof R¹⁰ and R¹¹ may vary depending on the position of the correspondingsubstituent in the relevant starting material.

BIOLOGICAL TESTING

1. In Vitro Kinase Activity Assay

The recombinant enzymes (CDK2/CyclinA, FLT3, JAK2 and JAK2 V617F) werepurchased from Invitrogen (Cat #PV3267, 3182, 4210 and 4347respectively). All assays were carried out in 384-well white microtiterplates using the PKLight assay system from Cambrex (East Rutherford,N.J.). This assay platform is essentially a luminometric assay for thedetection of ATP in the reaction using a luciferase-coupled reaction.For CDK2/Cyclin A assay, the reaction mixture consisted of the followingcomponents in 25 μL assay buffer (50 mM Hepes pH 7.5, 10 mM MgCl₂, 5 mMMnCl₂, 5 mM BGP, 1 mM DTT, 0.1 mM sodium orthovanadate), 1.4 μg/mL ofCDK2/Cyclin A complex, 0.5 μM of RbING substrate (Invitrogen, Cat#PV2939) and 0.5 μM of ATP. The compounds were tested at 8concentrations prepared from 4-fold serial dilution starting at 10 μM.The reaction was incubated at room temperature for 2 hr. 13 μL ofPKLight ATP detection reagent was added and the reaction was incubatedfor 10 min. Luminescence signals were detected on a multi-label platereader (Victor² V 1420, Perkin-Elmer). The other kinase assays wereidentical except for the following differences in reagents. For FLT3assays, the reaction contained 2.0 μg/mL FLT3 enzyme, 5 μM ofpoly(Glu,Tyr) substrate (Sigma, Cat #P0275) and 4 μM of ATP. For JAK2assays, the reaction contained 0.6 μg/mL of JAK2 enzyme, 2 μM ofpoly(Glu,Ala,Tyr) substrate (Sigma, Cat #P3899) and 0.2 μM of ATP. ForJAK2 V617F mutant assays, the reaction contained 8.0 μg/mL of JAK2mutant enzyme, 2 μM of poly(Glu,Ala,Tyr) substrate (Sigma, Cat #P3899)and 0.2 μM of ATP. The analytical software, Prism 4.0 (GraphPad SoftwarePte Ltd) was used to generate IC₅₀ values from the data. IC₅₀ is definedas the concentration of compound required for 50% inhibition of kinaseenzyme activity. IC₅₀ data are shown in Table 7 below.

TABLE 7 In vitro kinase activity assay IC₅₀ data JAK2 Compound V617F No.CDK2 FLT3 JAK2 mutant  6 +++ +++ +++ NT  7 + +++ + NT 13 ++ +++ +++ +++14 + +++ +++ +++ 15 ++ +++ +++ +++ 19 + +++ +++ +++ 20 + +++ +++ +++29 + +++ +++ +++ 32 ++ +++ +++ NT 33 + +++ +++ NT 36 ++ +++ +++ NT 38 ++++ +++ NT 40 + +++ +++ NT 46 ++ +++ +++ NT 48 + +++ +++ NT 50 + +++ +++NT 52 + +++ +++ NT 53 ++ +++ +++ NT 55 + +++ +++ NT 56 ++ +++ +++ NT NT= not tested IC₅₀ ≦ 1 μM +++ 1 μM < IC₅₀ ≦ 5 μM ++ IC₅₀ > 5 μM +2. Cell Lines

The cell lines used in the studies are summarized in Table 8 below:

TABLE 8 Characteristics of human cell lines used Basic culture Seedingdensity Cell lines Tumour origin Supplier medium (per well) HCT116 ColonATCC McCoy's 3,000 medium Colo205 Colon ATCC RPMI 1640 5,000 HL60 AMLATCC RPMI 1640 8,000 MV4-11 AML ATCC Iscove's MEM 6,000 HELErythroleukemia ATCC RPMI 1640 6,000 DU145 Prostate ATCC RPMI 6140 1,000U266 Myeloma DSMZ RPMI 6140 10,000  Karpas B-cell DSMZ RPMI 1640 10,000 Lymphoma3. Cell-Based Proliferation Assay for Determination of GI₅₀ Values

The biological efficacy of the invention was demonstrated by thefollowing assay. Human cancer cell lines HL60 (acute myeloid leukemiacell line), Colo205 (colon adenocarcinoma cell line), HEL92.1.7(erythroleukemia cell line) and MV4-11 (acute myeloid leukemia cellline) were obtained from ATCC. They were cultivated in the mediaaccording to the ATCC work instructions. Colo205 cells were seeded in96-wells plate at 5000 cells per well. HEL92.1.7 and MV4-11 cells wereseeded at 6000 cells per well while HL60 cells were seeded at 8000 cellsper well in 96 well plate. The plates were incubated at 37° C., 5% CO₂,for 24 h. Cells were treated with compounds at various concentrationsfor 96 h. Cell growth was then monitored using Celltiter96 Aqueous OneSolution Cell Proliferation Assay from Promega (Madison Wis.). Doseresponse curves were plotted to determine GI₅₀ values for the compoundsusing XL-fit (ID Business Solution, Emeryville, Calif.). GI₅₀ is definedas the concentration of compound required for 50% inhibition of cellgrowth. The compounds of this invention inhibited cell proliferation asshown in Table 9 below. The data indicated that the compounds of thisinvention are active in the inhibition of tumour cell growth.

TABLE 9 Cell-based proliferation assay GI₅₀ data HL60 Colo205 HEL92.1.7MV4-11  6 ++ ++ NT NT  7 +++ + + + 13 +++ ++ ++ +++ 14 +++ ++ +++ +++ 15+++ ++ ++ +++ 19 +++ +++ +++ +++ 20 ++ + + +++ 29 +++ NT ++ +++ 32 +++NT ++ +++ 33 ++ NT ++ +++ 36 +++ NT ++ +++ 38 +++ NT ++ +++ 40 +++ NT+++ +++ 46 +++ NT ++ +++ 48 +++ +++ +++ +++ 50 +++ NT ++ +++ 52 +++ NT+++ +++ 53 +++ NT ++ +++ 55 ++ NT ++ +++ 56 +++ NT ++ +++ NT = nottested GI₅₀ ≦ 1 μM +++ 1 μM < GI₅₀ ≦ 5 μM ++ GI₅₀ > 5 μM +In Vivo Antineoplastic (or Anti-Tumour) Effect:

The efficacy of the compounds of the invention can then be determinedusing in vivo animal xenograft studies. The animal xenograft model isone of the most commonly used in vivo cancer models.

In these studies Female athymic nude mice (Harlan), 12-14 weeks of agewould be implanted subcutaneously in the flank with 5×10⁶ cells ofMV4-11 human biphenotypic B myelomonocytic leukemia cells in Matrigel(BD Biosciences, in 1:1). When the tumour reaches the size 100 mm³, thexenograft nude mice would be paired-match into various treatment groups.The selected kinase inhibitors would be dissolved in appropriatevehicles and administered to xenograft nude mice intraperitoneally ororally daily for 21 days. The dosing volume will be 0.01 ml/g bodyweight. Tumour volume will be calculated every second day ortwice-a-week of post injection using the formula: Volume (mm³)=(w²×l)/2,where w=width and l=length in mm of a MV4-11 tumour. Compounds of thisinvention that are tested would show significant reduction in tumourvolume relative to controls treated with vehicle only. The result willtherefore indicate that compounds of this invention are efficacious intreating a proliferative disease such as cancer.

The details of specific embodiments described in this invention are notto be construed as limitations. Various equivalents and modificationsmay be made without departing from the essence and scope of thisinvention, and it is understood that such equivalent embodiments arepart of this invention.

What is claimed is:
 1. A method of treating a condition in a mammal inwhich inhibition of one or more protein kinase(s) inhibits a pathologyor a symptomology of the condition, the method comprising administrationof a therapeutically effective amount of a compound of the formula (I)

wherein: R¹ and R² are each independently selected from the groupconsisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy,heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy,heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino,sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³, —CONHR³, —NHCOR³,—NHCOOR³, —NHCONHR³, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl,—SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—,R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each ofwhich can be optionally substituted; each R³, R⁴, and R⁵ isindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl and acyl, each of which can be optionally substituted;each R⁶ is independently selected from the group consisting of a bond,alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each ofwhich can be optionally substituted; Z² is —N(R⁷); each R⁷ isindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl and acyl, each of which can be optionally substituted;Ar¹ and Ar² are both phenylene, each of which can be optionallysubstituted; L is a group of formula:—X¹—Y—X²— wherein X¹ is attached to Ar¹ and X² is attached to Ar², andwherein X¹, X² and Y are selected such that the group L has between 5and 15 atoms in the normal chain, X¹ and X² are each independently aheteroalkyl group containing at least one oxygen atom in the normalchain, Y is a group of formula —CR^(a)═CR^(b)—, wherein R^(a) and R^(b)are each independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl; cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl and acyl, each of which can be optionally substituted,or R^(a) and R^(b) can be joined such that when taken together with thecarbon atoms to which they are attached they form a cycloalkenyl orcycloheteroalkenyl group; or a pharmaceutically acceptable salt orN-oxide thereof; wherein the condition is selected from the groupconsisting of myelofibrosis, acute myeloid leukemia, colon cancer,glioblastoma multiforme, chronic myelomonocytic leukemia, and Hodgkin'sdisease.
 2. The method according to claim 1 wherein the one or moreprotein kinase(s) is a cyclin-dependent protein kinase.
 3. The methodaccording to claim 2 wherein the cyclin-dependent kinase is a Group ICMCG kinase.
 4. The method according to claim 3 wherein the Group I CMCGkinase is selected from the group consisting of CDC2Hs, CDK2, CDK3,CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2,Dm2c, Ddcdc2, DdPRK, LmmCRK1, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28,PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R.
 5. The method according toclaim 3 wherein the Group I CMCG kinase is CDK2.
 6. The method accordingto claim 1 wherein the one or more protein kinase(s) is a proteintyrosine kinase.
 7. The method according to claim 6 wherein the proteintyrosine kinase is a Group VII protein tyrosine kinase.
 8. The methodaccording to claim 7 wherein the Group VII protein tyrosine kinase isselected from the group consisting of TYK2, JAK1, JAK2 and HOP.
 9. Themethod according to claim 8 wherein the Group VII protein tyrosinekinase is JAK2.
 10. The method according to claim 9 wherein the JAK2includes a V to F mutation at position
 617. 11. The method according toclaim 6 wherein the protein tyrosine kinase is a Group XIV proteintyrosine kinase.
 12. The method according to claim 11 wherein the GroupXIV protein tyrosine kinase is selected from the group consisting ofPDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4.
 13. Themethod according to claim 12 wherein the Group XIV protein tyrosinekinase is FLT3.
 14. The method according to claim 13 wherein the FLT3includes an internal tandem duplication.
 15. The method according toclaim 14 wherein the internal tandem duplication is a duplication ofamino acids VDFREYEYDH at position 592-601.
 16. The method according toclaim 1 wherein the one or more protein kinase(s) include at least twokinases selected from the group consisting of CDK2, FLT3 and JAK2. 17.The method according to claim 16 wherein the one or more proteinkinase(s) include all three of CDK2, FLT3 and JAK2.
 18. A method oftreating a proliferative disorder comprising administration of atherapeutically effective amount of a compound of formula (I)

wherein: R¹ and R² are each independently selected from the groupconsisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl,heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy,alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,acylamino, arylamino, sulfonyl amino, sulfinylamino, —COOH, —COR³,—COOR³, —CONHR³, —NHCOR³, —NHCOOR³, —NHCONHR³, alkoxycarbonyl,alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—,R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—, R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—,R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each of which can be optionallysubstituted; each R³, R⁴, and R⁵ is independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each ofwhich can be optionally substituted; each R⁶ is independently selectedfrom the group consisting of a bond, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl andacyl, each of which can be optionally substituted; Z² is —N(R⁷)—; eachR⁷ is independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl and acyl, each of which can be optionally substituted;Ar¹ and Ar² are both phenylene, each of which can be optionallysubstituted; L is a group of formula:—X¹—Y—X²—; wherein X¹ is attached to Ar¹ and X² is attached to Ar², andwherein X¹, X² and Y are selected such that the group L has between 5and 15 atoms in the normal chain, X¹ and X² are each independently aheteroalkyl group containing at least one oxygen atom in the normalchain, Y is a group of formula —CR^(a)═CR^(b)—, wherein R^(a) and R^(b)are each independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl and acyl, each of which can be optionally substituted,or R^(a) and R^(b) can be joined such that when taken together with thecarbon atoms to which they are attached they form a cycloalkenyl orcycloheteroalkenyl group; or a pharmaceutically acceptable salt orN-oxide thereof; wherein the proliferative disorder is selected from thegroup consisting of myelofibrosis, acute myeloid leukemia, colon cancer,glioblastoma multiforme, chronic myelomonocytic leukemia, and Hodgkin'sdisease.
 19. The method according to claim 1 wherein in the compound offormula I Z² is —N(H)—.
 20. The method according to claim 1 wherein inthe compound of formula I Ar¹ is

wherein R¹⁰ is independently selected from the group consisting of: H,halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aryl alkyl,heteroaryl alkyl, aryl alkenyl, cycloalkylheteroalkyl,heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy,alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR³,—COOR³, —CONHR³, —NHCOR³, —NHCOOR³, —NHCONHR³, alkoxycarbonyl,alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—,R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—, R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—,R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each of which may be optionallysubstituted, k is an integer selected from the group consisting of 0, 1,2, 3, and
 4. 21. The method according to claim 1 wherein in the compoundof formula I Ar² is a group selected from the group consisting of:

wherein each R¹¹ is independently selected from the group consisting of:H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl,heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy,alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR³,—COOR³, —CONHR³, —NHCOR³, —NHCOOR³, —NHCONHR³, alkoxycarbonyl,alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—,R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—, R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—,R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each of which can be optionallysubstituted.
 22. The method according to claim 1 wherein in the compoundof formula I X¹ is selected from the group consisting of: (a) —OCH₂— (b)—CH₂O—, (c) —OCH₂CH₂—, (d) —CH₂CH₂O—, (e) —CH₂OCH₂—, and (f)—CH₂CH₂OCH₂—.
 23. The method according to claim 1 wherein in thecompound of formula I X² is selected from the group consisting of: (a)—OCH₂— (b) —CH₂O—, (c) —OCH₂CH₂—, (d) —CH₂CH₂O—, (e) —CH₂OCH₂—, and (f)—CH₂CH₂OCH₂—.
 24. The method according to claim 1 wherein in thecompound of formula I Y is selected from the group consisting of:


25. The method according to claim 1 wherein the compound of Formula (I)is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 26. The method accordingto claim 18 wherein in the compound of formula I Z² is —N(H)—.
 27. Themethod according to claim 18 wherein in the compound of formula I Ar¹ is

wherein R¹⁰ is independently selected from the group consisting of: H,halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl,heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy,alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR³,—COOR³, —CONHR³, —NHCOR³, —NHCOOR³, —NHCONHR³, alkoxycarbonyl,alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—,R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—, R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—,R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each of which can be optionallysubstituted, k is an integer selected from the group consisting of 0, 1,2, 3, and
 4. 28. The method according to claim 18 wherein in thecompound of formula I Ar² is a group selected from the group consistingof:

wherein each R¹¹ is independently selected from the group consisting of:H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy,heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy,heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino,sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³, —CONHR³, —NHCOR³,—NHCOOR³, —NHCONHR³, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl,—SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—,R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each ofwhich can be optionally substituted.
 29. The method according to claim18 wherein in the compound of formula I X¹ is selected from the groupconsisting of: (a) —OCH₂— (b) —CH₂O—, (c) —OCH₂CH₂—, (d) —CH₂CH₂O—, (e)—CH₂OCH₂—, and (f) —CH₂CH₂OCH₂—.
 30. The method according to claim 18wherein in the compound of formula I X² is selected from the groupconsisting of: (a) —OCH₂— (b) —CH₂O—, (c) —OCH₂CH₂—, (d) —CH₂CH₂O—, (e)—CH₂OCH₂—, and (f) —CH₂CH₂OCH₂—.
 31. The method according to claim 18wherein in the compound of formula I Y is selected from the groupconsisting of:


32. The method according to claim 18 wherein the compound of Formula (I)is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 33. The method accordingto claim 25 wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 34. The method accordingto claim 32 wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 35. The method accordingto claim 33 wherein the condition is myelofibrosis.
 36. The methodaccording to claim 34 wherein the proliferative disorder ismyelofibrosis.
 37. The method according to claim 18 wherein theproliferative disorder is myelofibrosis.
 38. The method according toclaim 18 wherein the proliferative disorder is acute myeloid leukemia.39. The method according to claim 18 wherein the proliferative disorderis colon cancer.
 40. The method according to claim 18 wherein theproliferative disorder is glioblastoma multiforme.
 41. The methodaccording to claim 18 wherein the proliferative disorder is chronicmyelomonocytic leukemia.
 42. The method according to claim 18 whereinthe proliferative disorder is Hodgkin's disease.
 43. The methodaccording to claim 1 wherein the condition is myelofibrosis.
 44. Themethod according to claim 1 wherein the condition is acute myeloidleukemia.
 45. The method according to claim 1 wherein the condition iscolon cancer.
 46. The method according to claim 1 wherein the conditionis glioblastoma multiforme.
 47. The method according to claim 1 whereinthe condition is chronic myelomonocytic leukemia.
 48. The methodaccording to claim 1 wherein the condition is Hodgkin's disease.